1stOncology™: Cancer Intelligence Service – Page 15873 – 1stOncology is recognized as a Top 10 Global Pharma Analytic Provider

Verastem Announces the Presentation of Phase 1 Duvelisib Combination Data in T-Cell Lymphomas at the ASH 2017 Annual Meeting

On December 11, 2017 Verastem, Inc. (NASDAQ: VSTM), focused on discovering and developing drugs to improve the survival and quality of life of cancer patients, reported the presentation of new preclinical and Phase 1 clinical data from an investigator-sponsored study evaluating the safety and activity of oral duvelisib in combination with romidepsin (Istodax) or bortezomib (Velcade) in relapsed or refractory T-cell lymphomas (TCL) at the American Society of Hematology (ASH) (Free ASH Whitepaper) 2017 Annual Meeting held December 9-12, 2017 in Atlanta (Press release, Verastem, DEC 11, 2017, View Source;p=RssLanding&cat=news&id=2322203 [SID1234522563]). Duvelisib is a first-in-class oral dual inhibitor of phosphoinositide-3-kinase (PI3K)-delta and PI3K-gamma which is currently being developed for the treatment of relapsed or refractory Chronic Lymphocytic Leukemia (CLL) and Small Lymphocytic Lymphoma (SLL) and Follicular Lymphoma (FL). In addition, duvelisib is being studied in other hematologic malignancies including both peripheral and cutaneous T cell lymphoma (TCL).

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

Schedule Your 30 min Free Demo!

"The data presented today at ASH (Free ASH Whitepaper) demonstrate that oral duvelisib, combined with either romidepsin or bortezomib, has an acceptable safety profile in patients with relapsed or refractory TCL with response rates, while still preliminary, that appear promising when compared to those seen with currently approved therapies," said Steven Horwitz, MD, Memorial Sloan Kettering Cancer Center (MSKCC), co-principal investigator of the Phase 1 study, and lead author of the oral presentation. "We were especially pleased to see that these response rates were even higher in patients with peripheral TCL (PTCL), a rare and aggressive type of non-Hodgkin lymphoma. These clinical results were further bolstered by important preclinical findings showing duvelisib’s cell killing activity in vitro and its ability to promote beneficial changes within the in vivo tumor microenvironment."

"The preclinical and Phase 1 results reported today by the team at MSKCC are important because they provide further validation for our continued expansion of the duvelisib development program into T-cell malignancies including PTCL," said Diep Le, MD, PhD, Chief Medical Officer of Verastem. "Overall, our data presentations at ASH (Free ASH Whitepaper) this year continue to build upon the strong foundation of preclinical research and clinical investigation for Verastem’s product candidates, demonstrating their anti-cancer activity, either alone or in combination with other agents, across a wide variety of hematologic malignancies."

Phase 1 Safety and Activity Results
This multicenter, Phase I trial is comprised of parallel arms evaluating oral duvelisib in combination with romidepsin (arm A) or bortezomib (arm B) in patients with relapsed/refractory TCL, including PTCL and cutaneous T-cell lymphoma (CTCL). Oral duvelisib was dosed at 25mg, 50mg, or 75mg twice-daily (BID) on days 1-28. Romidepsin 10mg/m2 was dosed on Days 1, 8, and 15 (arm A) or bortezomib 1mg/m2 on Days 1, 4, 8, and 11 (arm B), both cohorts on 28-day cycles.

In arm A, there were 15 patients evaluable for efficacy (PTCL, n=11; CTCL, n=4). Of these, nine responded (4 complete responses (CR) and 5 partial responses (PR) for an overall response rate (ORR) of 60%. Seven of the 11 patients with PTCL responded (4 CR and 3 PR) for an ORR of 64%. Among the 9 patients evaluable for safety (25mg, n=3; 50mg, n=3; 75mg, n=3), there were no dose limiting toxicities (DLT), therefore oral duvelisib 75mg BID in combination with romidepsin 10mg/m2 IV was defined as the maximum tolerated dose (MTD). The most common Grade 1/2 adverse events were fatigue (n=9), nausea (n=8), altered taste (n=8) and diarrhea (n=6), rash (n=5), dysphagia (n=4) and anorexia (n=4). The most common Grade 3/4 adverse events were neutropenia (n=6), thrombocytopenia (n=1), lung infection (n=1), pleural effusion (n=1) and hyponatremia (n=1). There were two deaths (sepsis and diffuse alveolar hemorrhage following allogeneic stem cell transplant) that were both assessed as unrelated to study drug.

In arm B, there were 17 patients evaluable for efficacy (PTCL, n=10; CTCL, n=7). Of these, six responded (3 CRs and 3 PRs) for an ORR of 35%. Five of the 10 patients with PTCL responded (3 CRs and 2 PRs) for an ORR of 50%. Among the 14 patients evaluable for safety (25mg, n=6; 50mg, n=3; 75mg, n=5), there was one DLT (pneumonia) in the 25mg group. The MTD was determined to be oral duvelisib 25mg BID in combination with bortezomib 1mg/m2 IV. The most common Grade 1/2 adverse events were diarrhea/colitis (n=11), nausea/vomiting (n=4), chills (n=4) and fatigue (n=4). The most common Grade 3/4 adverse events were ALT and AST elevation (n=6), rash (n=2) and neutropenia (n=2). There was a case of Stevens-Johnson syndrome resulting in death which was assessed by the investigator as possibly related to bortezomib, duvelisib, and trimethoprim-sulfamethoxazole, a medication that was initiated at the start of the study.

A copy of this oral presentation will be available here following the conclusion of the session.

About the Tumor Microenvironment
The tumor microenvironment encompasses various cellular populations and extracellular matrices within the tumor or cancer niche that support cancer cell survival. This includes immunosuppressive cell populations such as regulatory T-cells, myeloid-derived suppressor cells, M2 TAMS, as well as tumor-associated fibroblasts and extracellular matrix proteins which can hamper the entry and therapeutic benefit of cytotoxic immune cells and anti-cancer drugs. In addition to targeting the proliferative and survival signaling of cancer cells, Verastem’s compounds duvelisib and defactinib target the tumor microenvironment as a mechanism of action to potentially improve a patient’s response to therapy.

About Duvelisib
Duvelisib is a first-in-class investigational, dual inhibitor of phosphoinositide 3-kinase (PI3K)-delta and PI3K-gamma, two enzymes known to help support the growth and survival of malignant B-cells and T-cells. PI3K signaling may lead to the proliferation of malignant B- and T-cells and is thought to play a role in the formation and maintenance of the supportive tumor microenvironment.1,2,3 Duvelisib is currently being evaluated in late- and mid-stage extension trials, including DUO, a randomized, Phase 3 monotherapy study in patients with relapsed or refractory chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL),4 and DYNAMO, a single-arm, Phase 2 monotherapy study in patients with refractory indolent non-Hodgkin lymphoma (iNHL).5 Both DUO and DYNAMO achieved their primary endpoints and Verastem intends to submit a New Drug Application (NDA) requesting the full approval of duvelisib for the treatment of patients with relapsed or refractory CLL/SLL, and accelerated approval for the treatment of patients with relapsed or refractory follicular lymphoma (FL). Duvelisib is also being developed by Verastem for the treatment of peripheral T-cell lymphoma (PTCL), and is being investigated in combination with other agents through investigator-sponsored studies.6 Information about duvelisib clinical trials can be found on www.clinicaltrials.gov

About Focal Adhesion Kinase
Focal Adhesion Kinase (FAK) is a non-receptor tyrosine kinase encoded by the PTK-2 gene that is involved in cellular adhesion and, in cancer, metastatic capability. Defactinib (VS-6063) and VS-4718 are orally available compounds that are potent inhibitors of FAK. Defactinib and VS-4718 utilize a multi-faceted approach to treat cancer by reducing cancer stem cells, enhancing anti-tumor immunity, and modulating the local tumor microenvironment. Defactinib is currently being studied in multiple clinical trials for patients with cancer.

Kite Announces Data From ZUMA-3 Study of KTE-C19 in Adult Patients with Relapsed or Refractory Acute Lymphoblastic Leukemia

On December 11, 2017 Kite, a Gilead Company (Nasdaq: GILD), reported updated results from the ongoing Phase 1/2 ZUMA-3 study of KTE-C19, a CD19 chimeric antigen receptor T (CAR T) cell therapy, which is investigational for the treatment of adult patients with relapsed or refractory acute lymphoblastic leukemia (ALL) (Press release, Kite Pharma, DEC 11, 2017, View Source;p=irol-newsArticle&ID=2322221 [SID1234522565]). With a minimum of eight weeks of follow-up, 71 percent of ALL patients (n=17/24) who received a single infusion of KTE-C19 achieved complete tumor remission (complete remission (CR) or CR with incomplete hematological recovery). The ZUMA-3 study results were presented in an oral session at the Annual Meeting of the American Society of Hematology (ASH) (Free ASH Whitepaper) in Atlanta.

This press release features multimedia. View the full release here: View Source

ALL is an aggressive type of blood cancer which can also involve the lymph nodes, spleen, liver, central nervous system and other organs.

"Approximately half of new ALL cases occur in adults age 20 or older and a majority of adult ALL patients relapse and have poor subsequent outcomes," said Bijal Shah, MD, ZUMA-3 investigator and medical oncologist, Moffitt Cancer Center, Tampa, Fla. "The deep remissions seen with these early study results offer promise that adults with this aggressive disease may benefit from personalized cell therapy with KTE-C19. Pending further clinical evaluation, this has the potential to be an advance for adults with no other treatment options."

ZUMA-3 is an ongoing multicenter Phase 1/2 study in patients with ALL whose disease is refractory to or has relapsed following standard chemotherapy or hematopoietic stem cell transplantation. The objectives of the study are to evaluate the safety and efficacy of KTE-C19 in this patient population.

At the time of data cutoff, 24 patients were evaluable for response. KTE-C19 demonstrated a 71 percent (n=17/24) rate of complete remission, with 100 percent of responders having no detectable minimal residual disease, including in those with high tumor burden and high risk genetic abnormalities.

In the safety analysis of 29 patients, adverse events were consistent with the known toxicities of CD19 CAR T treatment, including Grade 3 or higher cytokine release syndrome (CRS) and neurologic toxicities in 28 percent (n=8/29) and 52 percent of patients (n=15/29), respectively. Two patients receiving KTE-C19 died due to adverse events, including one patient with a cerebrovascular accident not related to KTE-C19 treatment approximately seven weeks after treatment and a previously reported patient who experienced fatal CRS.

"We believe personalized cell therapy has the potential to become a cornerstone of cancer treatment and are rapidly advancing CAR T studies in ALL and in other cancers," said David Chang, MD, PhD, Worldwide Head of Research and Development and Chief Medical Officer at Kite. "ZUMA-3 is reflective of our continued commitment to cell therapy cancer treatment and we are pleased to see these early results for people living with ALL."

KTE-C19 for ALL is investigational and has not been proven safe or efficacious.

Gamida Cell Presents Data from Two Key Development Programs at the 2017 ASH Annual Meeting

On December 11, 2017 Gamida Cell, a leading cellular and immune therapeutics company, reported final results from the phase I/II trial evaluating NiCord, a product derived from cord blood stem cells, as a stand-alone graft to treat patients with high-risk hematologic malignancies (Press release, Gamida Cell, DEC 11, 2017, View Source [SID1234522566]). The study met its primary endpoint, demonstrating rapid neutrophil engraftment with manageable side effects. The company also presented preclinical data for the advancement of natural killer cells (NK cells) as an immunotherapeutic modality for patients with cancer. Both studies were presented today at the annual meeting of the American Society of Hematology (ASH) (Free ASH Whitepaper) in Atlanta, GA.

"We are enthusiastic about the data presented today at ASH (Free ASH Whitepaper), including the final results of our NiCord phase I/II study, which support the basis for our global phase III trial of NiCord versus standard unmanipulated cord blood transplantation (UCBT), currently enrolling patients with hematologic malignancies," said Julian Adams, Ph.D., chairman and chief executive officer of Gamida Cell. "We look forward to further evaluating the potential of NiCord to serve as the graft of choice for the thousands of patients with no matched donor in need of a transplant every year, as well as continuing to progress our other pipeline programs."

Final Data from Phase I/II Trial of NiCord.
The multicenter phase I/II study evaluated the safety and efficacy of NiCord as a stand-alone graft in 36 patients with high-risk hematologic malignancies, with a primary endpoint of time to neutrophil engraftment following transplantation. Despite varying blood cancer diagnoses and preparative conditioning regimens across patients across centers, improved results were seen in the majority of study participants treated with NiCord.

Final results of the study include the following:

Participants transplanted with NiCord had rapid and durable engraftment of neutrophils and platelets, as well as prompt immune reconstitution:
Median time to neutrophil engraftment was 11 days (95% CI: 9-13 days);
Median time to platelet engraftment was 34 days (95% CI: 32-42 days).
Results from the study participants were compared to a database of matched patients from the Center for International Blood and Marrow Transplant Research (CIBMTR). According to the CIBMTR data, patients who received UCBT had a median time to neutrophil engraftment of 21 days and a median time to platelet engraftment of 46 days.
NiCord demonstrated an acceptable safety profile, with moderate/severe chronic graft vs. host disease (cGvHD) in 9.8% of patients at one year following transplantation. By day 100, 20.2% of participants experienced grade 2-3 bacterial or grade 3 fungal infections.

"Historically, transplantation with cord blood has been limited due to slow engraftment time in patients. We are looking to address this gap, and this study demonstrated rapid and sustained engraftment in study participants by utilizing technology to expand the number of stem cord blood cells in a culture," said Mitchell Horwitz, M.D., principal investigator, co-study chair and professor of medicine at the Duke Cancer Institute. "These phase I/II data demonstrate the potential to make stem cell transplants accessible to a greater number of patients who do not have a matched donor."

Preclinical Data from NAM-NK Cell Program
Proof-of-concept data on the application of the company’s proprietary NAM technology to healthy donor natural killer cells (NK cells) as a potential immunotherapeutic approach to treating cancer were highlighted in an oral presentation.

"The use of NK cells as a modality for immunotherapy has been limited by impaired functionality of adoptively transferred NK cells in patients," said Ronit Simantov, M.D., chief medical officer at Gamida Cell. "We are encouraged by the study results, which demonstrated persistence and proliferation of NAM-NK cells in pre-clinical in vivo models and describe a reliable, scalable culture model for the expansion of functional donor NK cells aimed at clinical use."

The analysis, which combines data from multiple preclinical studies, validates the approach and is the basis for an investigator-sponsored, phase I clinical trial of NAM-NK Cells in patients with relapsed/refractory multiple myeloma or CD20-positive non-Hodgkin lymphoma.

About NiCord
NiCord, the company’s lead clinical program, is under development as a universal bone marrow transplant solution for patients with high-risk hematologic malignancies. NiCord has demonstrated improved efficacy over unmanipulated cord blood, including fewer bacterial and fungal infections and a reduction in duration of hospital stays. NiCord has been granted breakthrough status by the U.S. Food and Drug Administration, making it the first bone marrow transplant alternative to receive this designation. It has also received U.S. and EU orphan drug designation. The ongoing phase III study is evaluating NiCord as a curative treatment for patients with leukemia and lymphoma who have been indicated for an allogeneic stem cell transplant. For more information on NiCord clinical trials, please visit www.clinicaltrials.gov.

About NAM-NK Cells
Gamida Cell expanded the capabilities of its NAM technology to utilize NK cells to create an immunotherapy to treat patients with refractor blood cancers and solid tumors. Through expansion of highly functional NK cells using NAM technology, NAM-NK Cells can be used to harness the immune system to attack cancer. NAM-NK Cell is under phase I development (NCT03019666) in patients with relapsed or refractory B-cell lymphoma and multiple myeloma.

New Data from Ivosidenib Phase 1 Dose-Escalation and Expansion Trial Demonstrate Durable Responses in Patients with IDH1m Relapsed or Refractory AML

On December 11, 2017 Agios Pharmaceuticals, Inc. (NASDAQ:AGIO), a leader in the field of cellular metabolism to treat cancer and rare genetic diseases, reported new efficacy and safety data from the ongoing Phase 1 dose-escalation and expansion study evaluating oral ivosidenib (AG-120) in patients with relapsed or refractory acute myeloid leukemia (R/R AML) and an isocitrate dehydrogenase-1 (IDH1) mutation (Press release, Agios Pharmaceuticals, DEC 11, 2017, View Source [SID1234522571]). Ivosidenib is an investigational, first-in-class, oral, targeted inhibitor of the mutant IDH1 enzyme. Data in an oral session at the 2017 American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition demonstrated a complete response (CR) and CR with partial hematologic recovery (CRh) rate of 30.4% and an overall response rate (ORR) of 41.6% in the primary analysis set of 125 patients with R/R AML who received ivosidenib at 500 mg once daily and received their first dose at least 6 months prior to the May 12, 2017 analysis cutoff date. The CR+CRh rate is the primary endpoint of the study.

"New ivosidenib data from the expansion phase of the Phase 1 study is compelling and demonstrates impressive single-agent efficacy with durable responses in these high-risk relapsed or refractory AML patients," said Courtney DiNardo, M.D., lead investigator and assistant professor, department of leukemia at the University of Texas MD Anderson Cancer Center. "Important measures of clinical benefit for patients treated with ivosidenib were also observed and include increases in transfusion independence and a decrease in the frequency of comorbidities such as febrile neutropenia and infections in responding patients."

A total of 258 patients with advanced hematologic malignances and an IDH1 mutation were treated on the Phase 1 study, which included 78 patients in the dose-escalation portion and 180 patients from four dose-expansion Arms. Enrollment to the study is closed. This is the first presentation of data from the dose-expansion portion of the study. Safety data reported include all treated patients, and includes those who received ivosidenib at total daily doses ranging from 200 mg to 1200 mg in dose-escalation and 500 mg daily in dose expansion. A maximum tolerated dose was not reached in the dose-escalation portion of the trial. The primary analysis set is comprised of 125 R/R AML patients (92 patients from Arm 1 of the expansion and 33 patients from the dose-escalation who met the eligibility criteria for Arm 1 and received ivosidenib at 500 mg once daily) who were enrolled at least 6 months prior to the primary analysis cutoff date of May 12, 2017. The median age of these patients is 67 (ranging from 18-87), and the median number of prior regimens is two (ranging from one to six).

"These data form the core of the efficacy analysis for our ivosidenib NDA submission, which is on track for the end of the year," said Chris Bowden, M.D., chief medical officer of Agios. "We believe that these data validate the potential for ivosidenib to be a first-in-class therapy for patients with R/R AML and an IDH1 mutation."

Safety Data
A safety analysis conducted for all 258 treated patients as of the data cut-off showed that ivosidenib continues to demonstrate a favorable safety profile. The most common adverse events (AEs) regardless of causality were diarrhea (33.3%), leukocytosis (30.2%), nausea (29.5%), fatigue (28.7%) and febrile neutropenia (25.2%).

Among the 125 R/R AML patients from the primary analysis set, adverse events of interest were the following:

8% reported Grade ≥3 leukocytosis, which was managed with hydroxyurea. No cases were fatal.
8% reported Grade 3 QT prolongation. Ivosidenib was reduced in one patient and held in five patients (for any grade of QT prolongation), and no cases were Grade 4 or fatal.
9.6% reported IDH-differentiation syndrome (IDH-DS), which was managed with corticosteroids and diuretics. None were Grade 4 or fatal.
Efficacy Data
Data from 125 R/R AML patients from the primary analysis set demonstrated a combined CR+CRh rate of 30.4% [95% CI 22.5, 39.3], which is the primary endpoint of the study. The CR rate was 21.6% (27 of 125 patients) [95% CI 14.7, 29.8] and the CRh rate was 8.8% (11 of 125 patients). CRh (complete remission with partial hematological recovery) is defined as <5% of blasts in the bone marrow, no evidence of disease and partial recovery of peripheral blood counts (platelets >50,000/microliter and ANC >500/microliter).

Overall response rate (ORR) was 41.6% (52 of 125 patients).
Median duration of response was 9.3 months [95% CI 5.6, 18.3] for patients who achieved a CR, 8.2 months [95% CI 5.5, 12.0] for patients who achieved a CR/CRh and 6.5 months [95% CI 4.6, 9.3] for all patients who responded.
Median time to first response was 1.9 months (0.8-4.7) for all patients who responded, median time to CR was 2.8 months (0.9-8.3) for patients who achieved a CR, and median time to CR/CRh was 2.7 months (0.9-5.6) for patients who achieved a CR/CRh.
At the time of the data cut-off, median overall survival (OS) as observed in the study has not yet been reached for patients who achieved a CR/CRh. OS was 9.3 months [95% CI 3.7, 10.8] for non-CR/CRh responders, 3.9 months [95% CI 2.8, 5.8] for non-responders, and 8.8 months [95% CI 6.7, 10.2] overall.
Of the patients who were transfusion dependent at baseline and achieved a CR, 100% became independent of platelet transfusions and 84.6% became independent of red blood cell (RBC) transfusions during any 56-day post baseline period.
Of the patients who were transfusion dependent at baseline and achieved a CRh, 71.4% became independent of platelet transfusions and 75.0% became independent of RBC transfusions during any 56-day post baseline period. Transfusion independence was also seen among non-CR/CRh responders and non-responders. Non-CR/CRh responders include patients with CR with incomplete hematologic recovery (CRi), CR with incomplete platelet recovery (CRp) and morphologic leukemia-free state (MLFS) who are not CRh.
Response in Untreated AML and MDS
An efficacy analysis was also presented for 34 untreated AML patients not eligible for standard of care therapies in expansion Arm 2 and from dose escalation whose starting dose was 500 mg daily and 12 myelodysplastic syndrome (MDS) patients in expansion Arm 3 and from dose escalation whose starting dose was 500 mg daily.

Data from 34 untreated AML patients demonstrated a 55.9% ORR and a CR rate of 20.6%. The median duration of response was 9.2 months [95% CI 1.9, NE], and median duration of CR has not yet been reached.
Data from 12 MDS patients demonstrated a 91.7% ORR and a CR rate of 41.7%.
Clinical Development in AML
Ivosidenib continues to be studied in the following ongoing clinical trials in AML:

Phase 3 AGILE study evaluating the safety and efficacy of ivosidenib + azacitidine vs. placebo + azacitidine in adults with previously untreated IDH1m AML who are considered appropriate candidates for non-intensive therapy
Phase 1b study of either ivosidenib or enasidenib in combination with standard induction and consolidation chemotherapy in newly diagnosed AML
Phase 1/2 study of either ivosidenib or enasidenib in combination with azacitidine in newly diagnosed AML
Agios is on track to file a New Drug Application (NDA) for ivosidenib with the U.S. Food and Drug Administration by the end of 2017.

About the Phase 1 Trial for Ivosidenib in Advanced Hematologic Malignancies
Ivosidenib (AG-120) is being evaluated in an ongoing Phase 1 trial that includes a dose-escalation phase and four expansion arms, including:

Arm 1: IDH1 mutant positive AML patients who relapsed after bone marrow transplantation, are in second or later relapse, refractory to initial induction or reinduction treatment, or who relapse within one year of initial treatment, excluding patients with favorable-risk status
Arm 2: untreated IDH1 mutant positive AML patients who are not candidates for standard-of-care chemotherapy
Arm 3: patients with other non-AML IDH1 mutant, relapsed or refractory advanced hematologic malignancies
Arm 4: patients with relapsed IDH1 mutant positive AML not eligible for arm 1 who have failed or are unable to receive standard of care
About Acute Myelogenous Leukemia (AML)
AML, a cancer of blood and bone marrow characterized by rapid disease progression, is the most common acute leukemia affecting adults. Undifferentiated blast cells proliferate in the bone marrow rather than mature into normal blood cells. AML incidence significantly increases with age, and according to the American Cancer Society, the median age of onset is 66. The vast majority of patients do not respond to chemotherapy and progress to relapsed/refractory AML. The five-year survival rate for AML is approximately 20 to 25 percent. IDH1 mutations are present in about 6 to 10 percent of AML cases.

Investor Event and Webcast Information
Agios will host an investor event on Monday, December 11, 2017 beginning at 8:00 p.m. ET in Atlanta to review data presented at ASH (Free ASH Whitepaper). The event will be webcast live and can be accessed under "Events & Presentations" in the Investors section of the company’s website at www.agios.com.

Data from Phase 1 Studies of Ivosidenib or Enasidenib in Combination with Full Doses of Standard of Care Chemotherapy Demonstrate Tolerability and Preliminary Clinical Activity in Newly Diagnosed AML Patients With an IDH Mutation

On December 11, 2017 Agios Pharmaceuticals, Inc. (NASDAQ:AGIO), a leader in the field of cellular metabolism to treat cancer and rare genetic diseases, reported data from two studies evaluating ivosidenib (AG-120) and an investigational use of IDHIFA (enasidenib) in patients with newly diagnosed acute myeloid leukemia (AML) and an isocitrate dehydrogenase (IDH)1 or IDH2 mutation (Press release, Agios Pharmaceuticals, DEC 11, 2017, View Source [SID1234522573]). The data were presented as part of the scientific program at the 59thAmerican Society of Hematology Annual Meeting in Atlanta.

"The totality of the data presented at ASH (Free ASH Whitepaper) demonstrate the potential benefit of IDHm inhibitors in the frontline setting for patients with AML," said Eytan Stein, M.D., study investigator and attending physician in the leukemia service at Memorial Sloan Kettering Cancer Center. "The Phase 1 frontline combination trials showed that ivosidenib and enasidenib are well tolerated when combined with standard induction chemotherapy or azacitadine and both trials demonstrated early encouraging signs of efficacy. I look forward to evaluating both ivosidenib and enasidenib in late-stage, placebo-controlled clinical trials to understand the full impact of these medicines on newly diagnosed AML patients."

Combination with Standard Induction Chemotherapy
The first presentation, given by Dr. Stein, evaluated ivosidenib or enasidenib in combination with standard induction chemotherapy in patients with newly diagnosed AML and an IDH1 or IDH2 mutation. During induction, patients received either 500 mg of ivosidenib and 7 + 3 standard chemotherapy (daunorubicin 60 mg/m2/day or idarubicin 12 mg/m2/day x 3 days with cytarabine 200 mg/m2/day x 7 days) (n=32) or 100 mg of enasidenib and 7 + 3 standard chemotherapy (n=56). Of these patients, 69% in the ivosidenib arm and 57% in the enasidenib arm had de novo AML, while the remaining patients had secondary AML (sAML). For patients with sAML, 40% in the ivosidenib arm and 63% in the enasidenib arm had received prior hypomethylating agent therapy. After induction, patients could receive up to four cycles of consolidation chemotherapy while continuing ivosidenib or enasidenib. Patients who achieved a complete response (CR) or a complete response with incomplete neutrophil or platelet recovery (CRi/CRp) after consolidation could continue to take single agent ivosidenib or enasidenib daily for up to two years from day one of induction.

Ivosidenib Results
In the ivosidenib arm, the most common Grade 3 or higher non-hematologic adverse events during the induction period were febrile neutropenia (60%), blood bilirubin increased (9%), hypertension (9%), colitis (9%), increased alanine aminotransferase (9%) and increased aspartate aminotransferase (9%). The 30 and 60-day mortality rates were both 6%, and there were no dose-limiting toxicities. The median time to absolute neutrophil count (ANC) recovery (>500/µL) was 28.5 days (95% CI 27,34). Median time to platelet recovery (>50,000/µL) was 28 days (95% CI 26,34).

The CR+CRi/CRp rate for de novo patients was 91% (19/21) and 44% (4/9) for sAML patients. The overall best response of CR+ CRi/CRp rate for all patients was 77% (23/30).

Enasidenib Results
In the enasidenib arm, the most common Grade 3 or higher non-hematologic adverse events during the induction period were febrile neutropenia (63%), blood bilirubin increased (9%), hypertension (9%) and bacteremia (9%). The 30 and 60-day mortality rates were 5% and 7%, respectively. There was one dose-limiting toxicity in the enasidenib combination arm consisting of persistent Grade 4 thrombocytopenia lasting beyond 42 days from the start of induction. The median time to ANC recovery (>500/µL) was 34 days (95% CI 29,35). Median time to platelet recovery (>50,000/µL) was 33 days (95% CI 29,50).

The CR+CRi/CRp rate for de novo patients was 67% (18/27) and 57% (13/23) for sAML patients. The overall best response of CR+CRi/CRp rate for all patients was 62% (31/50).

"The early results from these studies of ivosidenib and enasidenib in combination with traditional frontline AML treatment are highly encouraging and support the strategy to advance IDHm inhibitors into the newly diagnosed setting," said Chris Bowden, M.D., chief medical officer of Agios. "We are focused on evaluating the IDHm inhibitors in late-stage studies that span the entire frontline setting with our ongoing Phase 3 AGILE study of ivosidenib in combination with azacitidine versus azacitidine and a planned Phase 3 study of ivosidenib and enasidenib in combination with 7+3 intensive chemotherapy."

Combination with Azacitidine
The second presentation, given by Courtney DiNardo, M.D., evaluated an investigational use of enasidenib or ivosidenib in combination with azacitidine in patients with newly diagnosed AML unable to receive intensive chemotherapy. In the study, patients received 100mg (n=3) or 200mg (n=3) of enasidenib daily plus azacitidine or 500 mg of ivosidenib (n=11) plus azacitidine. At the data cutoff, 11 patients remained on the study (3 enasidenib, 8 ivosidenib).

Enasidenib Results

For patients receiving the enasidenib combination, the most common Grade 3-4 hematologic adverse event was neutropenia (33%, 2/6). The most common Grade 3-4 non-hematologic adverse events were pneumonia (33%, 2/6) and hyperbilirubinemia (33%, 2/6). IDH differentiation syndrome was reported in one patient.

Four of six patients had a response, including two CRs, one partial response (PR) and one morphologic leukemia-free state (MLFS).

Ivosidenib Results
For patients receiving the ivosidenib combination, the most common Grade 3-4 hematologic adverse events were anemia (18%, 2/11) and febrile neutropenia (18%, 2/11) with neutropenia and thrombocytopenia each with one event (9% each). The most common Grade 3-4 non-hematologic adverse event was pneumonia (18%, 2/11). IDH differentiation syndrome was reported in one patient.

Eight of 11 patients had a response, including four CRs, one CRi, one PR and two MLFS.

Neither IDHIFA nor ivosidenib are approved for the treatment of patients with newly diagnosed AML or approved in combination with azacitidine.

About IDHIFA

IDHIFA (enasidenib) is indicated for the treatment of adult patients with relapsed or refractory acute myeloid leukemia with an isocitrate dehydrogenase-2 mutation as detected by an FDA-approved test.

Important Safety Information

WARNING: DIFFERENTIATION SYNDROME
Patients treated with IDHIFA have experienced symptoms of differentiation syndrome, which can be fatal if not treated. Symptoms may include fever, dyspnea, acute respiratory distress, pulmonary infiltrates, pleural or pericardial effusions, rapid weight gain or peripheral edema, lymphadenopathy, bone pain, 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, 14% of patients treated with IDHIFA experienced differentiation syndrome, which may be life-threatening or fatal if not treated. Differentiation syndrome has been observed with and without concomitant hyperleukocytosis, as early as 10 days and at up to 5 months after IDHIFA initiation. Symptoms in patients treated with IDHIFA included acute respiratory distress represented by dyspnea and/or hypoxia and need for supplemental oxygen; pulmonary infiltrates and pleural effusion; renal impairment; fever; lymphadenopathy; bone pain; peripheral edema with rapid weight gain; and pericardial effusion. Hepatic, renal, and multi-organ dysfunction have also been observed. If differentiation syndrome is suspected, initiate systemic corticosteroids and hemodynamic monitoring until improvement. Taper corticosteroids only after resolution of symptoms. Differentiation syndrome symptoms may recur with premature discontinuation of corticosteroids. If severe pulmonary symptoms requiring intubation or ventilator support and/or renal dysfunction persist for more than 48 hours after initiation of corticosteroids, interrupt IDHIFA until signs and symptoms are no longer severe. Hospitalization for close observation and monitoring of patients with pulmonary and/or renal manifestation is recommended.

Embryo-Fetal Toxicity: Based on animal embryo-fetal toxicity studies, IDHIFA can cause embryo-fetal harm when administered to a pregnant woman. Advise females of reproductive potential and males with female partners of reproductive potential to use effective contraception during treatment with IDHIFA and for at least 1 month after the last dose. Pregnant women, patients becoming pregnant while receiving IDHIFA, or male patients with pregnant female partners should be apprised of the potential risk to the fetus.

ADVERSE REACTIONS

The most common adverse reactions (≥20%) included total bilirubin increased (81%), calcium decreased (74%), nausea (50%), diarrhea (43%), potassium decreased (41%), vomiting (34%), decreased appetite (34%), and phosphorus decreased (27%)
The most frequently reported ≥Grade 3 adverse reactions (≥5%) included total bilirubin increased (15%), potassium decreased (15%), phosphorus decreased (8%), calcium decreased (8%), diarrhea (8%), differentiation syndrome (7%), non-infectious leukocytosis (6%), tumor lysis syndrome (6%), and nausea (5%)
Serious adverse reactions were reported in 77.1% of patients. The most frequent serious adverse reactions (≥2%) were leukocytosis (10%), diarrhea (6%), nausea (5%), vomiting (3%), decreased appetite (3%), tumor lysis syndrome (5%), and differentiation syndrome (8%). Differentiation syndrome events characterized as serious included pyrexia, renal failure acute, hypoxia, respiratory failure, and multi-organ failure
LACTATION
Many drugs are excreted in human milk and because of the potential for adverse reactions in breastfed infants, advise women not to breastfeed during treatment with IDHIFA and for at least 1 month after the last dose.

Please see full Prescribing Information, including Boxed WARNING.