On June 3, 2019 Agios Pharmaceuticals, Inc. (NASDAQ: AGIO), a leader in the field of cellular metabolism to treat cancer and rare genetic diseases, reported data from two Phase 1 studies evaluating TIBSOVO (ivosidenib) in adult patients with newly diagnosed acute myeloid leukemia (AML) and an isocitrate dehydrogenase-1 (IDH1) mutation who are ineligible for intensive chemotherapy (Press release, Agios Pharmaceuticals, JUN 3, 2019, View Source [SID1234536795]). The data were presented as part of the scientific program at the 2019 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting in Chicago.

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"Newly diagnosed AML patients who are not eligible for intensive chemotherapy are typically older or have comorbidities that can lead to a worse prognosis and poor outcomes," said Courtney DiNardo, M.D., lead investigator and associate professor, department of leukemia at the University of Texas MD Anderson Cancer Center. "With an additional six months of follow up since the last data cutoff in the Phase 1 combination study of TIBSOVO with azacitidine, it is encouraging to see a 12-month survival rate of 82% and a continued increase in CR+CRh rate to 70% and CR rate to 61%. In addition, the majority of patients with CR also had IDH1 mutation clearance, suggesting direct impact on the biology of IDH1 mutant AML."

"As the data from these frontline Phase 1 studies of TIBSOVO mature, the durability of response has continued to improve over time and demonstrates that treating these patients with an IDH1 inhibitor early in the disease has the potential to provide deep, durable responses," said Chris Bowden, M.D., chief medical officer at Agios. "The recent sNDA approval in newly diagnosed AML patients with an IDH1 mutation who are ineligible for intensive chemotherapy was the first step in our broad program to develop TIBSOVO across the frontline setting."

Phase 1 Study of TIBSOVO in Combination with Azacitidine

The ongoing Phase 1/2 study is evaluating an investigational use of TIBSOVO or IDHIFA (enasidenib) in combination with azacitidine in patients with newly diagnosed IDH mutant AML unable to receive intensive chemotherapy. As of the February 19, 2019 data cutoff, 23 patients received 500 mg of TIBSOVO daily plus azacitidine in the TIBSOVO arm of the Phase 1b portion of the study. Enrollment in the TIBSOVO arm is complete. As of the data cutoff, 10 (43%) patients remained on study, and the median number of treatment cycles was 15 (range 1-30). The median age was 76 years old, and 52% of patients were age 75 or older. Sixty-five percent of patients had de novo AML and 35% had secondary AML.

Safety Results

The most common Grade 3/4 adverse events (AEs) regardless of cause were thrombocytopenia (61%), anemia (44%), febrile neutropenia (44%) and neutropenia (30%).
Investigator reported IDH differentiation syndrome was reported in four patients, of which three were serious AEs. All four cases resolved, among whom two achieved a complete response (CR), one stable disease and one was not evaluable for response.
Mean neutrophil and platelet counts were maintained near or above thresholds for CR with partial hematologic recovery (CRh) while on study treatment with TIBSOVO and azacitidine. CRh is defined as <5% of blasts in the bone marrow, no evidence of disease and partial recovery of peripheral blood counts (ANC >500/microliter and platelets >50,000/microliter).
Efficacy Results

Overall, 78% (18/23) of patients had a response.
70% (16/23) of patients had a CR or CRh.
61% (14/23) of patients had a CR.
The median duration of CR (95% CI 9.3, NE) as well as CR+CRh (95% CI 12.2, NE) had not been reached.
The median time to response was 1.8 months (range 0.7-3.8 months) and the median time to CR was 3.7 months (range 0.8-15.7 months).
The 12-month survival rate was 82% (95% CI 58.8, 92.8).
The median duration of follow-up was 16.1 months (range 1.3-31.7 months).
For patients who achieved a CR, IDH1 mutation clearance was observed in 9 of 14 (64%) patients with available bone marrow mononuclear cells (BMMCs) and 11 of 14 patients (79%) with available peripheral blood mononuclear cells (PBMCs) as quantified by a digital PCR assay with lower limit of sensitivity for mutant IDH1 of 0.02-0.04% (or 10-4).
TIBSOVO is not approved in any country for the treatment of patients with newly diagnosed AML in combination with azacitidine.

Untreated AML Arm of Phase 1 Study of Single Agent TIBSOVO in IDH1 Mutant Hematologic Malignancies

As of the November 2, 2018 data cutoff, a total of 258 patients with advanced hematologic malignances and an IDH1 mutation were treated in the Phase 1 study, including 34 patients with untreated AML (nine from dose-escalation and 25 from expansion) who received 500 mg of TIBSOVO daily. Enrollment in the study is complete. The median treatment duration for the untreated AML patients was 4.3 months (0.3-40.9). The median age for these patients was 76.5 years (64-87) and 47% had received a prior hypomethylating agent. Among the untreated AML patients, 24% had de novo AML and 76% had secondary AML.

Safety Results

The most common AEs of any grade >25% regardless of causality were diarrhea (53%), fatigue (47%), nausea (38%), decreased appetite (35%), leukocytosis (26%), anemia (26%), edema peripheral (26%) and thrombocytopenia (26%).
Adverse events of interest were the following:
9% reported Grade ≥3 ECG QT prolongation. TIBSOVO was dose reduced in two patients and held in four patients (for any grade of ECG QT prolongation).
18% reported IDH differentiation syndrome of any grade, which was managed with corticosteroids and diuretics. Three patients had their dose temporarily held, and no patients required dose reductions.
3% reported Grade ≥3 leukocytosis.
No AEs of interest lead to any permanent treatment discontinuations or deaths.
Efficacy Results

Data from the 33 untreated AML patients with an IDH1 mutation confirmed by the Abbott RealTimeTM IDH1 assay demonstrated an overall response rate of 55% (18/33 patients).
42% (14/33) of patients had a CR or CRh.
30% (10/33) of patients had a CR.
The median duration of CR (95% CI 4.2, NE) as well as CR+CRh (95% CI 4.6, NE) had not been reached. The estimated 12-month durations of response were 78% for CR and 62% for CR+CRh.
Median overall survival was 12.6 months.
Among patients who were transfusion dependent at baseline, transfusion independence was observed across all response categories, where it was defined as an absence of transfusions for at least 56 consecutive days on treatment.
IDH1 mutation clearance, defined as a reduction in mIDH1 variant allele frequency to below the limit of detection of 0.02–0.04% (or 10-4), was observed in 64% (9/14) of patients who achieved CR+CRh, including 50% (5/10) of patients with CR and 100% (4/4) of patients with CRh.
About TIBSOVO (ivosidenib)
TIBSOVO is indicated for the treatment of acute myeloid leukemia (AML) with a susceptible isocitrate dehydrogenase-1 (IDH1) mutation as detected by an FDA-approved test in:

Adult patients with newly-diagnosed AML who are ≥75 years old or who have comorbidities that preclude use of intensive induction chemotherapy.
Adult patients with relapsed or refractory AML.
IMPORTANT SAFETY INFORMATION

WARNING: DIFFERENTIATION SYNDROME

Patients treated with TIBSOVO have experienced symptoms of differentiation syndrome, which can be fatal if not treated. Symptoms may include fever, dyspnea, hypoxia, pulmonary infiltrates, pleural or pericardial effusions, rapid weight gain or peripheral edema, hypotension, and hepatic, renal, or multi-organ dysfunction. If differentiation syndrome is suspected, initiate corticosteroid therapy and hemodynamic monitoring until symptom resolution.
WARNINGS AND PRECAUTIONS

Differentiation Syndrome: See Boxed WARNING. In the clinical trial, 25% (7/28) of patients with newly diagnosed AML and 19% (34/179) of patients with relapsed or refractory AML treated with TIBSOVO experienced differentiation syndrome. Differentiation syndrome is associated with rapid proliferation and differentiation of myeloid cells and may be life-threatening or fatal if not treated. Symptoms of differentiation syndrome in patients treated with TIBSOVO included noninfectious leukocytosis, peripheral edema, pyrexia, dyspnea, pleural effusion, hypotension, hypoxia, pulmonary edema, pneumonitis, pericardial effusion, rash, fluid overload, tumor lysis syndrome, and creatinine increased. Of the 7 patients with newly diagnosed AML who experienced differentiation syndrome, 6 (86%) patients recovered. Of the 34 patients with relapsed or refractory AML who experienced differentiation syndrome, 27 (79%) patients recovered after treatment or after dose interruption of TIBSOVO. Differentiation syndrome occurred as early as 1 day and up to 3 months after TIBSOVO initiation and has been observed with or without concomitant leukocytosis.

If differentiation syndrome is suspected, initiate dexamethasone 10 mg IV every 12 hours (or an equivalent dose of an alternative oral or IV corticosteroid) and hemodynamic monitoring until improvement. If concomitant noninfectious leukocytosis is observed, initiate treatment with hydroxyurea or leukapheresis, as clinically indicated. Taper corticosteroids and hydroxyurea after resolution of symptoms and administer corticosteroids for a minimum of 3 days. Symptoms of differentiation syndrome may recur with premature discontinuation of corticosteroid and/or hydroxyurea treatment. If severe signs and/or symptoms persist for more than 48 hours after initiation of corticosteroids, interrupt TIBSOVO until signs and symptoms are no longer severe.

QTc Interval Prolongation: Patients treated with TIBSOVO can develop QT (QTc) prolongation and ventricular arrhythmias. One patient developed ventricular fibrillation attributed to TIBSOVO. Concomitant use of TIBSOVO with drugs known to prolong the QTc interval (e.g., anti-arrhythmic medicines, fluoroquinolones, triazole anti-fungals, 5-HT3 receptor antagonists) and CYP3A4 inhibitors may increase the risk of QTc interval prolongation. Conduct monitoring of electrocardiograms (ECGs) and electrolytes. In patients with congenital long QTc syndrome, congestive heart failure, or electrolyte abnormalities, or in those who are taking medications known to prolong the QTc interval, more frequent monitoring may be necessary.

Interrupt TIBSOVO if QTc increases to greater than 480 msec and less than 500 msec. Interrupt and reduce TIBSOVO if QTc increases to greater than 500 msec. Permanently discontinue TIBSOVO in patients who develop QTc interval prolongation with signs or symptoms of life-threatening arrhythmia.

Guillain-Barré Syndrome: Guillain-Barré syndrome occurred in <1% (2/258) of patients treated with TIBSOVO in the clinical study. Monitor patients taking TIBSOVO for onset of new signs or symptoms of motor and/or sensory neuropathy such as unilateral or bilateral weakness, sensory alterations, paresthesias, or difficulty breathing. Permanently discontinue TIBSOVO in patients who are diagnosed with Guillain-Barré syndrome.

ADVERSE REACTIONS

The most common adverse reactions including laboratory abnormalities (≥20%) were hemoglobin decreased (60%), fatigue (43%), arthralgia (39%), calcium decreased (39%), sodium decreased (39%), leukocytosis (38%), diarrhea (37%), magnesium decreased (36%), edema (34%), nausea (33%), dyspnea (32%), uric acid increased (32%), potassium decreased (32%), alkaline phosphatase increased (30%), mucositis (28%), aspartate aminotransferase increased (27%), phosphatase decreased (25%), electrocardiogram QT prolonged (24%), rash (24%), creatinine increased (24%), cough (23%), decreased appetite (22%), myalgia (21%), constipation (20%), and pyrexia (20%).
In patients with newly diagnosed AML, the most frequently reported Grade ≥3 adverse reactions (≥5%) were fatigue (14%), differentiation syndrome (11%), electrocardiogram QT prolonged (11%), diarrhea (7%), nausea (7%), and leukocytosis (7%). Serious adverse reactions (≥5%) were differentiation syndrome (18%), electrocardiogram QT prolonged (7%), and fatigue (7%). There was one case of posterior reversible encephalopathy syndrome (PRES).
In patients with relapsed or refractory AML, the most frequently reported Grade ≥3 adverse reactions (≥5%) were differentiation syndrome (13%), electrocardiogram QT prolonged (10%), dyspnea (9%), leukocytosis (8%), and tumor lysis syndrome (6%). Serious adverse reactions (≥5%) were differentiation syndrome (10%), leukocytosis (10%), and electrocardiogram QT prolonged (7%). There was one case of progressive multifocal leukoencephalopathy (PML).
DRUG INTERACTIONS

Strong or Moderate CYP3A4 Inhibitors: Reduce TIBSOVO dose with strong CYP3A4 inhibitors. Monitor patients for increased risk of QTc interval prolongation.
Strong CYP3A4 Inducers: Avoid concomitant use with TIBSOVO.
Sensitive CYP3A4 Substrates: Avoid concomitant use with TIBSOVO.
QTc Prolonging Drugs: Avoid concomitant use with TIBSOVO. If co-administration is unavoidable, monitor patients for increased risk of QTc interval prolongation.

LACTATION

Because many drugs are excreted in human milk and because of the potential for adverse reactions in breastfed children, advise women not to breastfeed during treatment with TIBSOVO and for at least 1 month after the last dose.

Please see full Prescribing Information, including Boxed WARNING.

About Acute Myeloid Leukemia (AML)
AML is a cancer of the blood and bone marrow marked by rapid disease progression and is the most common acute leukemia affecting adults with approximately 20,000 new cases estimated in the U.S. each year. AML patients are typically older or have comorbidities that preclude the use of intensive chemotherapy. These patients typically have a worse prognosis and poor outcomes. The majority of patients with AML eventually relapse. The five-year survival rate is approximately 28%. For 6 to 10 percent of AML patients, the mutated IDH1 enzyme blocks normal blood stem cell differentiation, contributing to the genesis of acute leukemia. IDH1 mutations have been associated with negative prognosis in AML.

On June 3, 2019 PharmaCyte Biotech, Inc. (OTCQB: PMCB), a clinical stage biotechnology company focused on developing targeted cellular therapies for cancer and diabetes using its signature live-cell encapsulation technology, Cell-in-a-Box, reported that its Chief Executive Officer, Kenneth L. Waggoner, and PharmaCyte’s consultant cellular biologist, David Judd, will be on site at Austrianova’s GMP manufacturing facility in Bangkok, Thailand, as the production of its clinical trial material for the treatment of locally advanced, non-metastatic, inoperable pancreatic cancer (LAPC) is underway (Press release, PharmaCyte Biotech, JUN 3, 2019, View Source [SID1234536811]).

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Mr. Waggoner and Mr. Judd will observe the culturing of the genetically altered HEK-293 cells both before and after they are encapsulated. Mr. Judd has a broad array of experience in development of cell culture media for many primary cells and cell lines and is particularly knowledgeable in the growth of HEK-293 cells. He has developed manufacturing processes, cell assays, biochemical analysis, cell culture processes and downstream recovery strategies. Although Mr. Judd has already offered advice to both PharmaCyte and Austrianova via telephonic communications, his actual on-site presence should prove to be invaluable. Mr. Judd will lend assistance in helping correct any unforeseen problems in the production process as the latest two staggered manufacturing "runs" are carried out and completed.

PharmaCyte’s Chief Executive Officer, Kenneth L. Waggoner, said, "After the changes to the manufacturing process allowed us to get back on track and proceed with GMP production of the "CypCaps," our clinical trial product for the company’s planned clinical trial in LAPC, I felt it was necessary to be on-site with David, our consulting expert in the culture of HEK-293 cells, to oversee the process and ensure we are staying on the path and clinical trial development timeline that we’ve developed to submit our Investigational New Drug application (IND). His presence will be particularly important since this time two manufacturing runs will be performed in a staggered fashion rather than consecutively as has been done in the past."

While in Thailand, Mr. Waggoner, Mr. Judd, Prof. Dr. Walter H. Günzburg and Dr. Brian Salmons of Austrianova and possibly others will be interviewed on the progress of the production, the testing of the clinical trial product, factors involved in the manufacturing process that will be included in the submission of the IND and various other topics related to the company’s planned clinical trial in LAPC.

While on-site at the GMP facility in Thailand, the company expects to post pictures, videos and interviews on its social media platforms. Shareholders and others who are interested in PharmaCyte’s content, should follow the company’s social media platforms:

Follow PharmaCyte on Facebook at: View Source
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On June 3, 2019 Epizyme, Inc. (Nasdaq: EPZM), a late-stage biopharmaceutical company developing novel epigenetic therapies, reported updated data on tazemetostat from the epithelioid sarcoma cohort of its ongoing Phase 2 study in patients with molecularly defined solid tumors (Press release, Epizyme, JUN 3, 2019, View Source [SID1234536832]). The data will be presented today in an oral presentation entitled "Safety and efficacy of tazemetostat, a first-in-class EZH2 inhibitor, in patients with epithelioid sarcoma" at the 2019 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting by Silvia Stacchiotti, M.D., Fondazione IRCCS Istituto Nazionale Tumori, Milan, and an investigator in the Phase 2 clinical trial.

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In July 2017, Epizyme completed enrollment of 62 patients in the epithelioid sarcoma cohort of its Phase 2 trial. Updated data reported today from that cohort are as of a September 17, 2018 cutoff date. Findings include that treatment with tazemetostat resulted in a 15% objective response rate (ORR) and a 26% disease control rate (DCR). The median duration of response (DOR) has not yet been reached. Among the 62 patients, tazemetostat continues to be generally well-tolerated with favorable safety.

"Today, there are limited effective and tolerable treatment options available for patients with epithelioid sarcoma, a rare and aggressive cancer that affects people in the prime of their lives," said Dr. Shefali Agarwal, chief medical officer of Epizyme. "We are pleased that the data presented today are consistent with what we have seen throughout our development of tazemetostat for epithelioid sarcoma, demonstrating meaningful clinical activity and good tolerability. Importantly, the totality of these data formed the foundation for our first NDA submission, which we just announced last week. If we are successful, tazemetostat would be the first FDA-approved EZH2 inhibitor. We are thankful to the patients, physicians and caregivers who have participated in our study and hope that tazemetostat may positively impact patients with this devastating cancer in the future."

Efficacy Data
The epithelioid sarcoma cohort in Epizyme’s Phase 2 study represents the largest prospective study of epithelioid sarcoma with any approved or investigational anticancer treatment to date. Epithelioid sarcoma is an ultra-rare and aggressive soft tissue sarcoma, characterized by a loss of the INI1 protein. It is most commonly diagnosed in young adults (20-40 years old) and is often fatal, with a median overall survival (OS) of less than one year in patients with metastatic disease.

The fully enrolled cohort includes 24 treatment-naive patients and 38 relapsed and/or refractory patients for a total of 62 adult and pediatric epithelioid sarcoma patients (at least 16 years of age). Patients enrolled were administered 800 mg of tazemetostat orally twice daily. The primary endpoint of the study is ORR, comprised of complete and partial responses as measured by RECIST 1.1. Secondary endpoints include DOR, DCR, OS and safety.

Updated findings are summarized below, based on a September 17, 2018 data cut-off date.

Key Efficacy Endpoint

Treatment-naive
(n=24)

Relapsed and/or
Refractory

(n=38)

Total
(n=62)

Objective Response Rate, n (%) 6 (25%) 3 (8%) 9 (15%)
Median Duration of Response, weeks
41.1
(34.1, not reached)

Not reached
(40.1, not reached)

Not reached
(34.1, not reached)

Disease Control Rate*, n (%)
(95% confidence interval)

10 (42%)
(22.1, 63.4)

6 (16%)
(6.0, 31.3)
16 (26%)
(15.5, 38.5)

Median Overall Survival, weeks
(95% confidence interval)

Not reached 47.4
(29.0, 68.1)

82.4
(47.4, not reached)

*Comprised of confirmed objective responses for any duration or disease stabilization of 32 weeks or more

Tazemetostat Safety Data
Favorable safety and tolerability have been observed with tazemetostat in this Phase 2 study cohort. The majority of treatment-emergent adverse events (TEAEs) were grade 1 or 2, with only 13 percent of patients experiencing grade 3 or higher treatment-related TEAEs. Reported TEAEs regardless of attribution with an incidence of 10% or greater were fatigue (39%), nausea (35%), cancer pain (32%), decreased appetite (26%), constipation (21%), vomiting (24%), cough and headache (18% each), diarrhea, weight decrease and anemia (16% each), dyspnea (13%) and plural effusion (11.% ). Two percent of patients were dose-reduced due to an adverse event and one patient discontinued treatment due to an adverse event in the Phase 2 cohort.

The safety data from the 62 epithelioid sarcoma patients in the study cohort are consistent with the overall safety observed to date in over 800 people in the tazemetostat clinical program.

Tazemetostat NDA Submission for Epithelioid Sarcoma
In May, Epizyme announced that it submitted the New Drug Application (NDA) for tazemetostat for the treatment of patients with metastatic or locally advanced epithelioid sarcoma not eligible for curative surgery to the US. Food and Drug Administration (FDA). The FDA has a 60-day filing review period to determine whether the NDA is complete and acceptable for filing.

About Epithelioid Sarcoma
Epithelioid sarcoma is an ultra-rare soft tissue sarcoma characterized by a loss of the protein INI1. Patients are most commonly diagnosed as young adults, between 20 and 40 years of age. Median overall survival from initial diagnosis is 30 months. Epithelioid sarcoma becomes more aggressive after recurrence or metastases, with a typical survival of less than one year for patients with metastatic disease.

About the Tazemetostat Clinical Trial Program
Tazemetostat, an oral, potent, first-in-class EZH2 inhibitor, is currently being studied as a monotherapy in ongoing clinical programs in patients with certain molecularly defined solid tumors, including epithelioid sarcoma and other INI1-negative tumors, and in patients with follicular lymphoma, both with and without EZH2 activating mutations. Multiple clinical studies are underway through collaborations assessing tazemetostat as a combination treatment for patients with diffuse large B-cell lymphoma. Epizyme also plans to conduct multiple additional clinical trials designed to evaluate the potential benefit of tazemetostat in earlier lines of therapy for follicular lymphoma, as well as new combinations and cancer indications.

On June 3, 2019 AIVITA Biomedical, Inc., a biotech company specializing in innovative stem cell applications, reported that Chief Medical Officer Dr. Robert O. Dillman presented clinical data on melanoma patients treated with patient-specific vaccines on June 1 at the 55th Annual Meeting of ASCO (Free ASCO Whitepaper) in Chicago, Illinois (Press release, AIVITA Biomedical, JUN 3, 2019, View Source [SID1234536849]). The data is being published concurrently in the journal Melanoma Management.

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The abstract and publication describe survival data for 72 patients pooled from two Phase 2 trials. In the first trial conducted in 54 patients, the projected median overall survival was 54% at a time when median follow up was 4.5 years (Dillman et al. Cancer Biother Radiopahrm 2009;24:311-319.). Actual 5-year survival was 50% once all patients had been followed a minimum of five years. In the second Phase 2 trial patients were randomized for treatment with either their patient-specific dendritic cell vaccine (DCV) or patient-specific tumor cell vaccine (TCV). In both treatment arms the source of antigen was autologous tumor cells that were self-renewing in cell culture. Median overall survival was better in the DCV-treated patients: median survival 40.3 vs 20.5 months, 3-year actual survival of 61% vs 25% (p=0.018), and a 70% reduction in the risk of death (p=0.0053) [Dillman et al. J Immunother Cancer 2018;6:19.] The data for DCV-treated patients was pooled in order to address questions related to survival of specific subsets of patients [Dillman et al. Melanoma Manag 2019]. All patients had been followed for five years. The data showed that for melanoma patients who had recurrent Stage III disease that was not measurable at the time DCV-treatment was initiated, the 5-year survival rate was 72%. In melanoma patients who had previous Stage IV melanoma but did not have measurable disease at the time of treatment, the 5-year survival rate was 53%. Patients with measurable Stage IV melanoma had a median survival of 18.5 months with a two-year survival rate of 46%, which compares favorably to results achieved with anti-PD-1 checkpoint inhibitors in similar patients.

AIVITA is currently conducting three clinical studies investigating its platform ROOT OF CANCER therapy in patients with ovarian cancer, glioblastoma and melanoma. AIVITA uses 100% of proceeds from the sale of its ROOT of SKIN skincare line to support the treatment of women with ovarian cancer.

About ROOT OF CANCER

AIVITA’s treatment is a platform technology applicable to most solid tumor types and consists of autologous dendritic cells loaded with autologous tumor antigens from purified autologous self-renewing tumor-initiating cells.

OVARIAN CANCER:

AIVITA’s ovarian Phase 2 double-blind study is active and enrolling approximately 99 patients who are being randomized in a 2:1 ratio to receive either the autologous cancer stem cell-targeting immunotherapy or autologous monocytes as a comparator.

Patients eligible for randomization and treatment will be those (1) who have undergone debulking surgery, (2) for whom a cell line has been established, (3) who have undergone leukapheresis from which sufficient monocytes were obtained, (4) have an ECOG performance grade of 0 or 1 (Karnofsky score of 70-100%), and (5) who have completed primary therapy. The trial is not open to patients with recurrent ovarian cancer.

For additional information about AIVITA’s AVOVA-1 trial patients can visit: www.clinicaltrials.gov/ct2/show/NCT02033616

GLIOBLASTOMA:

AIVITA’s glioblastoma Phase 2 single-arm study is active and is enrolling approximately 55 patients to receive the cancer stem cell-targeting immunotherapy.

Patients eligible for treatment will be those (1) who have recovered from surgery such that they are about to begin concurrent chemotherapy and radiation therapy (CT/RT), (2) for whom an autologous tumor cell line has been established, (3) have a Karnofsky Performance Status of > 70 and (4) have undergone successful leukapheresis from which peripheral blood mononuclear cells (PBMC) were obtained that can be used to generate dendritic cells (DC). The trial is not open to patients with recurrent glioblastoma.

For additional information about AIVITA’s AV-GBM-1 trial please visit: www.clinicaltrials.gov/ct2/show/NCT03400917

MELANOMA:

AIVITA’s melanoma Phase 1B open-label, single-arm study will establish the safety of administering anti-PD1 monoclonal antibodies in combination with the cancer stem cell-targeting immunotherapy in patients with measurable metastatic melanoma. The study will also track efficacy of the treatment for the estimated 14 to 20 patients. This trial is not yet open for enrollment.

Patients eligible for treatment will be those (1) for whom a cell line has been established, (2) who have undergone leukapheresis from which sufficient monocytes were obtained, (3) have an ECOG performance grade of 0 or 1 (Karnofsky score of 70-100%), (4) who have either never received treatment for metastatic melanoma or were previously treated with enzymatic inhibitors of the BRAF/MEK pathway because of BRAF600E/K mutations and (5) are about to initiate anti-PD1 monotherapy.

For additional information about AIVITA’s AV-MEL-1 trial please visit: www.clinicaltrials.gov/ct2/show/NCT03743298

On June 3, 2019 Takeda Pharmaceutical Company Limited (TSE:4502/NYSE:TAK) reported that new data for TAK-788 will be presented during an oral session at the 2019 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting on Monday, June 3 at 10:12 a.m. CT in Chicago (Press release, Takeda, JUN 3, 2019, View Source [SID1234536882]). Results from a Phase 1/2 first-in-human, open-label, multicenter study showed TAK-788 yielded a median progression-free survival (PFS) of 7.3 months and a confirmed objective response rate (ORR) of 43% in patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) whose tumors harbor epidermal growth factor receptor (EGFR) exon 20 insertion mutations. These findings add to the collection of data featured at this year’s meeting from Takeda’s lung cancer portfolio, which also revealed key insights from sub-analyses of ALUNBRIG (brigatinib), including quality of life data from the Phase 3 ALTA-1L (ALK in Lung Cancer Trial of BrigAtinib in 1st Line) trial. TAK-788 is an investigational drug for which efficacy and safety have not been established. ALUNBRIG does not yet have regulatory approval for first-line therapy.

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"We are thrilled to share promising, early results from TAK-788, an investigational therapy that has the potential to help advance the treatment of NSCLC patients with EGFR exon 20 insertion mutations," said Phil Rowlands, Ph.D., Head, Oncology Therapeutic Area Unit, Takeda. "Furthermore, meaningful insights from our ongoing ALUNBRIG Phase 3 clinical trial, ALTA-1L, will be unveiled during the meeting. ALUNBRIG is the only treatment of its kind to report improved quality of life over another ALK tyrosine kinase inhibitor (TKI) as evidenced by patient-reported outcomes presented at ASCO (Free ASCO Whitepaper). These findings build upon our ALTA-1L efficacy data and illustrate ALUNBRIG’s potential to provide a meaningful benefit for patient’s life quality."

Results from the Phase 1/2 trial of TAK-788 will be presented on Monday, June 3 at 10:12 a.m. CT in Hall B1 of the McCormick Place Convention Center. A summary of key findings is provided below:

The current analysis evaluated a total of 28 NSCLC patients with EGFR exon 20 insertions who were treated with the recommended Phase 2 dose (RP2D) of 160 mg once daily. More than 50% of patients had received three or more prior regimens and 61% had been previously treated with an immune-checkpoint inhibitor. The median time on treatment was 7.9 months ongoing.
Among the total patients treated, including those with brain metastases at baseline, 43% (n=12/28) had a confirmed objective response and median PFS was 7.3 months. Patients without brain metastases at baseline had a confirmed objective response of 56% (n=9/16) and a median PFS of 8.1 months.
The disease control rate was 86% (n=24/28) for the total patients treated and 100% for patients without brain metastases at baseline (n=16/16).
The safety profile of TAK-788 was manageable. For patients treated at the 160 mg once daily dose:
The most common any grade treatment-related adverse events (AEs) were diarrhea (85%), nausea (43%), rash (36%), vomiting (29%) and decreased appetite (25%).
Most treatment-related AEs were Grade 1-2 and reversible.
Forty percent experienced Grade ≥3 treatment-related AEs.
The most common Grade ≥3 treatment-related AEs were diarrhea (18%), nausea (6%), increased lipase (6%), increased amylase (4%) and stomatitis (4%).
Food instructions have been included in the ongoing study with the potential to improve gastrointestinal tolerability.
At the time of the analysis, 50% of patients were still on treatment, and additional results will be presented at future congresses, including those from the recently opened Phase 2 pivotal extension cohort, EXCLAIM. The pivotal cohort was designed to evaluate the efficacy and safety of TAK-788 at 160 mg once daily in previously treated patients and will build upon the results seen in the Phase 1/2 trial.
"Results from this Phase 1/2 trial show that TAK-788 effectively treated NSCLC patients whose tumors harbor EGFR exon 20 insertion mutations and who had been previously treated with multiple prior therapies," said Pasi A Jänne, M.D., Ph.D., Dana-Farber Cancer Institute. "These data represent an important development and demonstrate progress in addressing an unmet need for these patients, who currently have limited treatment options and no approved targeted therapies."

For ALUNBRIG, Takeda presented three posters featuring results from ongoing trials of its clinical development program, which seeks to expand Takeda’s research of ALUNBRIG and optimize its use among patients with anaplastic lymphoma kinase-positive (ALK+) NSCLC.

Notably, two posters highlighted sub-analyses of the Phase 3 ALTA-1L trial in patients who had not received prior treatment with an ALK inhibitor:

Results from an analysis of the validated patient-reported outcomes questionnaire EORTC QLQ-C30 showed that ALUNBRIG significantly improved the overall health-related quality of life (HRQoL) compared to crizotinib. Results also showed improvements for patients receiving ALUNBRIG across functional scales, with significant improvement seen for physical, emotional and cognitive functions. There was also observed improvement for symptom scales including fatigue, nausea and vomiting, appetite loss and constipation.
Additionally, an investigation of outcomes in patients of Asian versus non-Asian heritage demonstrated that ALUNBRIG showed improvement in PFS compared to crizotinib for both patient subgroups. The safety profile of ALUNBRIG in these subgroups was consistent with what has been reported previously, with no new safety concerns. These findings add to the body of evidence evaluating ALUNBRIG in the first-line setting for patients with ALK+ NSCLC.
About EGFR Exon 20 Insertion-Mutant NSCLC

Non-small cell lung cancer (NSCLC) is the most common form of lung cancer, accounting for approximately 85% of the estimated 1.8 million new cases of lung cancer diagnosed each year worldwide, according to the World Health Organization.1,2 Epidermal growth factor receptor (EGFR) is one of several unique, genetic alternations found in NSCLC that affects approximately 15-21% of all NSCLC patients.3,4 The exon refers to the location of the EGFR mutations, which can be found in exon 18, 19, 20 or 21. Exon 20 insertions are much less common than EGFR mutations in other exons, comprising approximately 6% of all EGFR-mutated lung tumors.5 Therefore, patients with NSCLC who harbor EGFR exon 20 insertion mutations make up a small proportion of the NSCLC population, and there are currently no targeted therapy options to treat them, as approved EGFR tyrosine kinase inhibitor (TKIs) were not designed for patients with this subtype of EGFR mutations.

About TAK-788

TAK-788 is a potent and selective next-generation, small-molecule tyrosine kinase inhibitor (TKI) intelligently designed and under clinical investigation to inhibit epidermal growth factor receptor (EGFR) and human EGFR 2 (HER2) exon 20 mutations with selectivity over wild type (WT) EGFR. Non-clinical studies demonstrated antitumor activity against de novo mutations in EGFR including EGFR exon 20 insertions and the acquired resistance mutation T790M. In October 2018, the ongoing Phase 1/2 trial of TAK-788 was amended to add the pivotal extension cohort, EXCLAIM, which was designed to evaluate the efficacy and safety of TAK-788 at 160 mg once daily in previously treated patients with EGFR exon 20 insertions and is currently actively recruiting.

The TAK-788 development program has started first in the non-small cell lung cancer (NSCLC) population and is expected to expand to additional underserved populations in other tumor types. TAK-788 is an investigational drug for which efficacy and safety have not been established.

About ALK+ NSCLC

Non-small cell lung cancer (NSCLC) is the most common form of lung cancer, accounting for approximately 85% of the estimated 1.8 million new cases of lung cancer diagnosed each year worldwide, according to the World Health Organization.1,2 Genetic studies indicate that chromosomal rearrangements in anaplastic lymphoma kinase (ALK) are key drivers in a subset of NSCLC patients. Approximately three to five percent of patients with metastatic NSCLC have a rearrangement in the ALK gene.6,7,8

Takeda is committed to continuing research and development in NSCLC to improve the lives of the approximately 40,000 patients diagnosed with this serious and rare form of lung cancer worldwide each year.9

About ALUNBRIG (brigatinib)

ALUNBRIG is a potent and selective next-generation tyrosine kinase inhibitor (TKI) that was designed to target and inhibit the anaplastic lymphoma kinase (ALK) fusion protein in non-small cell lung cancer (NSCLC).

In April 2017, ALUNBRIG received Accelerated Approval from the U.S. Food and Drug Administration (FDA) for anaplastic lymphoma kinase-positive (ALK+) metastatic NSCLC patients who have progressed on or are intolerant to crizotinib. This indication is approved under Accelerated Approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.
In July 2018, Health Canada approved ALUNBRIG for the treatment of adult patients with ALK+ metastatic NSCLC who have progressed on or who were intolerant to an ALK inhibitor (crizotinib).
In November 2018, the European Commission (EC) granted marketing authorization for ALUNBRIG as a monotherapy for the treatment of adult patients with ALK+ advanced NSCLC previously treated with crizotinib. The FDA, Health Canada and EC approvals of ALUNBRIG were primarily based on results from the pivotal Phase 2 ALTA (ALK in Lung Cancer Trial of AP26113) trial.
ALUNBRIG received Breakthrough Therapy Designation from the FDA for the treatment of patients with ALK+ NSCLC whose tumors are resistant to crizotinib and was granted Orphan Drug Designation by the FDA for the treatment of ALK+ NSCLC, ROS1+ and EGFR+ NSCLC.

The brigatinib clinical development program further reinforces Takeda’s ongoing commitment to developing innovative therapies for people living with ALK+ NSCLC worldwide and the healthcare professionals who treat them. The comprehensive program includes the following clinical trials:

Phase 1/2 trial, which was designed to evaluate the safety, tolerability, pharmacokinetics and preliminary anti-tumor activity of ALUNBRIG.
Pivotal Phase 2 ALTA trial investigating the efficacy and safety of ALUNBRIG at two dosing regimens in patients with ALK+ locally advanced or metastatic NSCLC who had progressed on crizotinib.
Phase 3 ALTA-1L, global, randomized trial assessing the efficacy and safety of ALUNBRIG in comparison to crizotinib in patients with ALK+ locally advanced or metastatic NSCLC who have not received prior treatment with an ALK inhibitor.
Phase 2 J-ALTA, single-arm, multicenter trial in Japanese patients with ALK+ NSCLC, focusing on patients who have progressed on alectinib. This trial is now enrolling.
Phase 2 ALTA 2, global, single-arm trial evaluating ALUNBRIG in patients with advanced ALK+ NSCLC who have progressed on alectinib or ceritinib. This trial is now enrolling.
Phase 3 ALTA 3, global randomized trial comparing the efficacy and safety of ALUNBRIG versus alectinib in participants with ALK+ NSCLC who have progressed on crizotinib. This trial is now enrolling.
For additional information on the brigatinib clinical trials, please visit www.clinicaltrials.gov.

ALUNBRIG IMPORTANT SAFETY INFORMATION

WARNINGS AND PRECAUTIONS

Interstitial Lung Disease (ILD)/Pneumonitis: Severe, life-threatening, and fatal pulmonary adverse reactions consistent with interstitial lung disease (ILD)/pneumonitis have occurred with ALUNBRIG. In Trial ALTA (ALTA), ILD/pneumonitis occurred in 3.7% of patients in the 90 mg group (90 mg once daily) and 9.1% of patients in the 90→180 mg group (180 mg once daily with 7-day lead-in at 90 mg once daily). Adverse reactions consistent with possible ILD/pneumonitis occurred early (within 9 days of initiation of ALUNBRIG; median onset was 2 days) in 6.4% of patients, with Grade 3 to 4 reactions occurring in 2.7%. Monitor for new or worsening respiratory symptoms (e.g., dyspnea, cough, etc.), particularly during the first week of initiating ALUNBRIG. Withhold ALUNBRIG in any patient with new or worsening respiratory symptoms, and promptly evaluate for ILD/pneumonitis or other causes of respiratory symptoms (e.g., pulmonary embolism, tumor progression, and infectious pneumonia). For Grade 1 or 2 ILD/pneumonitis, either resume ALUNBRIG with dose reduction after recovery to baseline or permanently discontinue ALUNBRIG. Permanently discontinue ALUNBRIG for Grade 3 or 4 ILD/pneumonitis or recurrence of Grade 1 or 2 ILD/pneumonitis.

Hypertension: In ALTA, hypertension was reported in 11% of patients in the 90 mg group who received ALUNBRIG and 21% of patients in the 90→180 mg group. Grade 3 hypertension occurred in 5.9% of patients overall. Control blood pressure prior to treatment with ALUNBRIG. Monitor blood pressure after 2 weeks and at least monthly thereafter during treatment with ALUNBRIG. Withhold ALUNBRIG for Grade 3 hypertension despite optimal antihypertensive therapy. Upon resolution or improvement to Grade 1 severity, resume ALUNBRIG at a reduced dose. Consider permanent discontinuation of treatment with ALUNBRIG for Grade 4 hypertension or recurrence of Grade 3 hypertension. Use caution when administering ALUNBRIG in combination with antihypertensive agents that cause bradycardia.

Bradycardia: Bradycardia can occur with ALUNBRIG. In ALTA, heart rates less than 50 beats per minute (bpm) occurred in 5.7% of patients in the 90 mg group and 7.6% of patients in the 90→180 mg group. Grade 2 bradycardia occurred in 1 (0.9%) patient in the 90 mg group. Monitor heart rate and blood pressure during treatment with ALUNBRIG. Monitor patients more frequently if concomitant use of drug known to cause bradycardia cannot be avoided. For symptomatic bradycardia, withhold ALUNBRIG and review concomitant medications for those known to cause bradycardia. If a concomitant medication known to cause bradycardia is identified and discontinued or dose adjusted, resume ALUNBRIG at the same dose following resolution of symptomatic bradycardia; otherwise, reduce the dose of ALUNBRIG following resolution of symptomatic bradycardia. Discontinue ALUNBRIG for life-threatening bradycardia if no contributing concomitant medication is identified.

Visual Disturbance: In ALTA, adverse reactions leading to visual disturbance including blurred vision, diplopia, and reduced visual acuity, were reported in 7.3% of patients treated with ALUNBRIG in the 90 mg group and 10% of patients in the 90→180 mg group. Grade 3 macular edema and cataract occurred in one patient each in the 90→180 mg group. Advise patients to report any visual symptoms. Withhold ALUNBRIG and obtain an ophthalmologic evaluation in patients with new or worsening visual symptoms of Grade 2 or greater severity. Upon recovery of Grade 2 or Grade 3 visual disturbances to Grade 1 severity or baseline, resume ALUNBRIG at a reduced dose. Permanently discontinue treatment with ALUNBRIG for Grade 4 visual disturbances.

Creatine Phosphokinase (CPK) Elevation: In ALTA, creatine phosphokinase (CPK) elevation occurred in 27% of patients receiving ALUNBRIG in the 90 mg group and 48% of patients in the 90 mg→180 mg group. The incidence of Grade 3-4 CPK elevation was 2.8% in the 90 mg group and 12% in the 90→180 mg group. Dose reduction for CPK elevation occurred in 1.8% of patients in the 90 mg group and 4.5% in the 90→180 mg group. Advise patients to report any unexplained muscle pain, tenderness, or weakness. Monitor CPK levels during ALUNBRIG treatment. Withhold ALUNBRIG for Grade 3 or 4 CPK elevation. Upon resolution or recovery to Grade 1 or baseline, resume ALUNBRIG at the same dose or at a reduced dose.

Pancreatic Enzyme Elevation: In ALTA, amylase elevation occurred in 27% of patients in the 90 mg group and 39% of patients in the 90→180 mg group. Lipase elevations occurred in 21% of patients in the 90 mg group and 45% of patients in the 90→180 mg group. Grade 3 or 4 amylase elevation occurred in 3.7% of patients in the 90 mg group and 2.7% of patients in the 90→180 mg group. Grade 3 or 4 lipase elevation occurred in 4.6% of patients in the 90 mg group and 5.5% of patients in the 90→180 mg group. Monitor lipase and amylase during treatment with ALUNBRIG. Withhold ALUNBRIG for Grade 3 or 4 pancreatic enzyme elevation. Upon resolution or recovery to Grade 1 or baseline, resume ALUNBRIG at the same dose or at a reduced dose.

Hyperglycemia: In ALTA, 43% of patients who received ALUNBRIG experienced new or worsening hyperglycemia. Grade 3 hyperglycemia, based on laboratory assessment of serum fasting glucose levels, occurred in 3.7% of patients. Two of 20 (10%) patients with diabetes or glucose intolerance at baseline required initiation of insulin while receiving ALUNBRIG. Assess fasting serum glucose prior to initiation of ALUNBRIG and monitor periodically thereafter. Initiate or optimize anti-hyperglycemic medications as needed. If adequate hyperglycemic control cannot be achieved with optimal medical management, withhold ALUNBRIG until adequate hyperglycemic control is achieved and consider reducing the dose of ALUNBRIG or permanently discontinuing ALUNBRIG.

Embryo-Fetal Toxicity: Based on its mechanism of action and findings in animals, ALUNBRIG can cause fetal harm when administered to pregnant women. There are no clinical data on the use of ALUNBRIG in pregnant women. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective non-hormonal contraception during treatment with ALUNBRIG and for at least 4 months following the final dose. Advise males with female partners of reproductive potential to use effective contraception during treatment and for at least 3 months after the last dose of ALUNBRIG.

ADVERSE REACTIONS

Serious adverse reactions occurred in 38% of patients in the 90 mg group and 40% of patients in the 90→180 mg group. The most common serious adverse reactions were pneumonia (5.5% overall, 3.7% in the 90 mg group, and 7.3% in the 90→180 mg group) and ILD/pneumonitis (4.6% overall, 1.8% in the 90 mg group and 7.3% in the 90→180 mg group). Fatal adverse reactions occurred in 3.7% of patients and consisted of pneumonia (2 patients), sudden death, dyspnea, respiratory failure, pulmonary embolism, bacterial meningitis and urosepsis (1 patient each).

The most common adverse reactions (≥25%) in the 90 mg group were nausea (33%), fatigue (29%), headache (28%), and dyspnea (27%) and in the 90→180 mg group were nausea (40%), diarrhea (38%), fatigue (36%), cough (34%), and headache (27%).

DRUG INTERACTIONS

CYP3A Inhibitors: Avoid coadministration of ALUNBRIG with strong or moderate CYP3A inhibitors. Avoid grapefruit or grapefruit juice as it may also increase plasma concentrations of brigatinib. If coadministration of a strong or moderate CYP3A inhibitor cannot be avoided, reduce the dose of ALUNBRIG.

CYP3A Inducers: Avoid coadministration of ALUNBRIG with strong or moderate CYP3A inducers. If coadministration of moderate CYP3A inducers cannot be avoided, increase the dose of ALUNBRIG

CYP3A Substrates: Coadministration of ALUNBRIG with sensitive CYP3A substrates, including hormonal contraceptives, can result in decreased concentrations and loss of efficacy of sensitive CYP3A substrates.

USE IN SPECIFIC POPULATIONS

Pregnancy: ALUNBRIG can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus.

Lactation: There are no data regarding the secretion of brigatinib in human milk or its effects on the breastfed infant or milk production. Because of the potential adverse reactions in breastfed infants, advise lactating women not to breastfeed during treatment with ALUNBRIG.

Females and Males of Reproductive Potential:

Pregnancy Testing: Verify pregnancy status in females of reproductive potential prior to initiating ALUNBRIG

Contraception: Advise females of reproductive potential to use effective non-hormonal contraception during treatment with ALUNBRIG and for at least 4 months after the final dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with ALUNBRIG and for at least 3 months after the final dose.

Infertility: ALUNBRIG may cause reduced fertility in males.

Pediatric Use: The safety and effectiveness of ALUNBRIG in pediatric patients have not been established.

Geriatric Use: Clinical studies of ALUNBRIG did not include sufficient numbers of patients aged 65 years and older to determine whether they respond differently from younger patients.

Hepatic or Renal Impairment: No dose adjustment is recommended for patients with mild or moderate hepatic impairment or mild or moderate renal impairment. Reduce the dose of ALUNBRIG for patients with severe hepatic impairment or severe renal impairment.

Please see the full U.S. Prescribing Information for ALUNBRIG at www.ALUNBRIG.com