On June 17, 2019 Verastem, Inc. (Nasdaq:VSTM) (Verastem Oncology or the Company), a biopharmaceutical company focused on developing and commercializing medicines seeking to improve the survival and quality of life of cancer patients, reported that two posters highlighting clinical data for COPIKTRA (duvelisib) in patients with relapsed or refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) were presented at the European Hematology Association (EHA) (Free EHA Whitepaper) 2019 Annual Meeting which took place June 13-16, 2019, in Amsterdam (Press release, Verastem, JUN 17, 2019, View Source;p=irol-newsArticle&ID=2401532 [SID1234537118]). One poster describes results from a post-hoc analysis evaluating the effect of COPIKTRA on lymphocytosis in patients with relapsed or refractory CLL/SLL from the Phase 3 DUO study, including patients with high-risk factors. The other poster describes dose modification data from patients with relapsed or refractory CLL/SLL in the DUO study.

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COPIKTRA, a targeted oral inhibitor of phosphoinositide 3-kinase (PI3K), and the first approved dual inhibitor of PI3K-delta and PI3K-gamma, received approval as monotherapy from the U.S. Food and Drug Administration (FDA) in September 2018 for the treatment of patients with relapsed or refractory CLL/SLL after at least two prior therapies.

"Duvelisib is a potent oral dual inhibitor of PI3K-delta and -gamma with clinical activity in patients with CLL/SLL after at least two prior therapies," said Hagop Youssoufian, MSc, M.D., Head of Medical Strategy at Verastem Oncology. "In a post-hoc analysis authored by Dr. Barrientos and colleagues, duvelisib induced rapid and transient lymphocytosis that was associated with a reduction in lymphadenopathy, including in high-risk patients. Notably, duvelisib also resulted in resolution of lymphocytosis at up to 21 weeks, and the majority of patients achieved a lymph node response and also achieved rapid shrinkage of their lymph nodes."

Patterns of Duvelisib-Induced Lymphocytosis in Patients with Relapsed/Refractory CLL/SLL, Including Those with High-Risk Factors

In this study, researchers aimed to characterize the clinical profile and kinetics associated with duvelisib-related lymphocytosis. Lymphocytosis is an increase in the number of lymphocytes (white blood cells) in the blood and is a recognized biological marker of treatment with B-cell receptor pathway inhibitors. Similar to ibrutinib and idelalisib, duvelisib treatment induces lymphocytosis in patients with CLL. This post hoc analysis defined response in patients (n=158) with relapsed or refractory CLL/SLL, including high-risk subgroups, which were characterized by unmutated IGHV (n=110), 17p deletion/TP53 mutation (n=48), 11q deletion (n=38), and bulky disease (n=74).

Of 158 patients treated with duvelisib, 78% experienced lymphocytosis. Median time to onset of lymphocytosis was one week across all patients, including patients in the high-risk subgroups. Median time to resolution of lymphocytosis was 14 weeks, with a 50% reduction from baseline at 21 weeks. Similar results were observed regardless of high-risk status. Rapid shrinkage of lymph nodes was noted, with 86% of patients achieving lymph node response. Among patients who achieved a response with duvelisib at first or second assessment, 78% and 86%, respectively, experienced lymphocytosis; median time to resolution of lymphocytosis in these patients was 12 and 18 weeks, respectively. Prolonged lymphocytosis (for >12 months) occurred in 12 patients (8%). The overall response rate in patients with prolonged lymphocytosis was 83%. Of note, the median PFS was similar among patients with and without prolonged lymphocytosis; 22.1 months (95% CI, 12.9-27.6), compared to 24 months (95% CI, 20.5-NE), respectively. Overall, there were low rates of tumor lysis syndrome (1 patient; 0.6%). These results showed that duvelisib monotherapy induced rapid and transient lymphocytosis temporally associated with a reduction in lymphadenopathy in patients with relapsed or refractory CLL/SLL.

Effect of Dose Modification on Response to COPIKTRA in Patients with Relapsed or Refractory CLL/SLL in the Phase 3 DUO Study

The randomized, multicenter, open-label, Phase 3 DUO study, compared COPIKTRA versus ofatumumab in 319 adult patients with CLL (n=312) or SLL (n=7) after at least one prior therapy. The study randomized patients with a 1:1 ratio to receive either COPIKTRA 25mg twice daily until disease progression or unacceptable toxicity, or ofatumumab, an approved standard of care treatment for use in CLL/SLL, for 7 cycles. This analysis examined dose modification patterns and their impact on response to COPIKTRA. Dose interruptions or dose reductions to 15mg, 10mg or 5mg twice daily were permitted per study protocol to manage treatment-emergent adverse events (TEAEs). Responses were assessed per an Independent Review Committee.

Among the 158 COPIKTRA-treated patients in the DUO study, the median duration of exposure was 11.6 months, versus 5.3 months for patients treated with ofatumumab. The most common cause of dose interruption was diarrhea (23%), followed by neutropenia (12%) and pneumonia or colitis (11% each). Among responders (n=118), median time to first response on COPIKTRA was 1.9 months and the estimated median duration of response was 11.1 months. Median time to first dose interruption was 3.9 months and median duration of dose interruption was 15 days (range 1 to 133 days). Response to COPIKTRA was improved or maintained in most patients evaluated for response who had at least one dose interruption for >1 week (84%) or >2 weeks (82%) followed by at least 3 weeks on COPIKTRA. In a landmark analysis, median PFS was similar in patients with dose interruptions and those without dose interruptions for >1 week (17.8 versus 16.3 months) or >2 weeks (17.8 versus 16.3 months) within the first 3 months. The median time to dose reduction after a complete response or partial response was 5.6 months (n=25) and median duration was 3.4 months. Median time to onset across adverse events of special interest (AESIs) after starting COPIKTRA ranged from 2.2 to 4.3 months. Median time to resolution was within 4 weeks across AESIs. Proportions of patients experiencing AESIs were stable or decreased over time after 3-6 months: 0-3 months, 64%; >3-6 months, 63%; >6-9 months, 47%; >9-12 months, 52%, and seldom led to discontinuation of COPIKTRA (≤10%). These findings support the thesis that dose interruptions or dose reductions may be useful in managing TEAEs with COPIKTRA and that dose interruptions of >1-2 weeks or more did not appear to significantly impact response to COPIKTRA or PFS.

PDF copies of these poster presentations are available here.

Details for the EHA (Free EHA Whitepaper) 2019 poster presentations are as follows:

Title: Effect of dose modifications on response to duvelisib in patients with relapsed/refractory (R/R) CLL/SLL in the DUO trial
Lead author: Paolo Ghia, Università Vita-Salute San Raffaele
Session: 6. Chronic lymphocytic leukemia and related disorders – Clinical
Abstract #: PS1157
Title: Patterns of duvelisib-induced lymphocytosis in patients with relapsed/refractory chronic lymphocytic leukemia/small lymphocytic leukemia including those with high-risk factors treated in the DUO trial
Lead author: Jacqueline Barrientos, Zucker School of Medicine at Hofstra/Northwell
Session: 6. Chronic lymphocytic leukemia and related disorders – Clinical
Abstract #: PS1160
Important Safety Information

WARNING: FATAL AND SERIOUS TOXICITIES: INFECTIONS, DIARRHEA OR COLITIS, CUTANEOUS REACTIONS, and PNEUMONITIS

•Fatal and/or serious infections occurred in 31% of COPIKTRA-treated patients. Monitor for signs and symptoms of infection. Withhold COPIKTRA if infection is suspected.

•Fatal and/or serious diarrhea or colitis occurred in 18% of COPIKTRA-treated patients. Monitor for the development of severe diarrhea or colitis. Withhold COPIKTRA.

•Fatal and/or serious cutaneous reactions occurred in 5% of COPIKTRA-treated patients. Withhold COPIKTRA.

•Fatal and/or serious pneumonitis occurred in 5% of COPIKTRA-treated patients. Monitor for pulmonary symptoms and interstitial infiltrates. Withhold COPIKTRA.

WARNINGS AND PRECAUTIONS

Infections: Serious, including fatal (4%), infections occurred in 31% of patients receiving COPIKTRA (N=442). The most common serious infections were pneumonia, sepsis, and lower respiratory infections. Median time to onset of any grade infection was 3 months, with 75% of cases occurring within 6 months. Treat infections prior to initiation of COPIKTRA. Advise patients to report new or worsening signs and symptoms of infection. Cases of Pneumocystis jirovecii pneumonia (PJP) (1%) and cytomegalovirus (CMV) reactivation/infection (1%) occurred in patients taking COPIKTRA. Provide prophylaxis for PJP during treatment and following completion of treatment until the absolute CD4+ T cell count is greater than 200 cells/µL. Consider prophylactic antivirals during COPIKTRA treatment to prevent CMV infection including CMV reactivation.

Diarrhea or Colitis: Serious, including fatal (<1%), diarrhea or colitis occurred in 18% of patients receiving COPIKTRA (N=442). Median time to onset of any grade diarrhea or colitis was 4 months, with 75% of cases occurring by 8 months. The median event duration was 0.5 months. Advise patients to report any new or worsening diarrhea.

Cutaneous Reactions: Serious, including fatal (<1%), cutaneous reactions occurred in 5% of patients receiving COPIKTRA (N=442). Fatal cases included drug reaction with eosinophilia and systemic symptoms (DRESS) and toxic epidermal necrolysis (TEN). Median time to onset of any grade cutaneous reaction was 3 months with a median event duration of 1 month. Presenting features for the serious events were primarily described as pruritic, erythematous, or maculo-papular. Less common presenting features include exanthem, desquamation, erythroderma, skin exfoliation, keratinocyte necrosis, and papular rash. Advise patients to report new or worsening cutaneous reactions.

Pneumonitis: Serious, including fatal (<1%), pneumonitis without an apparent infectious cause occurred in 5% of patients receiving COPIKTRA (N=442). Median time to onset of any grade pneumonitis was 4 months with 75% of cases occurring within 9 months. The median event duration was 1 month with 75% of cases resolving by 2 months.

Hepatotoxicity: Grade 3 and 4 ALT and/or AST elevation developed in 8% and 2%, respectively, of patients receiving COPIKTRA (N=442). Two percent of patients had both an ALT or AST > 3 X ULN and total bilirubin > 2 X ULN. Median time to onset of any grade transaminase elevation was 2 months with a median event duration of 1 month. Monitor hepatic function during treatment with COPIKTRA.

Neutropenia: Grade 3 or 4 neutropenia occurred in 42% of patients receiving COPIKTRA (N=442), with Grade 4 neutropenia occurring in 24% of all patients. Median time to onset of grade ≥3 neutropenia was 2 months. Monitor neutrophil counts at least every 2 weeks for the first 2 months of COPIKTRA therapy, and at least weekly in patients with neutrophil counts < 1.0 Gi/L (Grade 3-4).

Embryo-Fetal Toxicity: COPIKTRA can cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus and conduct pregnancy testing before initiating COPIKTRA treatment. Advise females of reproductive potential and males with female partners of reproductive potential to use effective contraception during treatment and for at least 1 month after the last dose.

ADVERSE REACTIONS

B-cell Malignancies Summary

Fatal adverse reactions within 30 days of the last dose occurred in 8% (36/442) of patients treated with COPIKTRA 25 mg BID. Serious adverse reactions were reported in 289 patients (65%). The most frequent serious adverse reactions that occurred were infection (31%), diarrhea or colitis (18%), pneumonia (17%), rash (5%), and pneumonitis (5%). The most common adverse reactions (reported in ≥20% of patients) were diarrhea or colitis, neutropenia, rash, fatigue, pyrexia, cough, nausea, upper respiratory infection, pneumonia, musculoskeletal pain and anemia.

CLL/SLL

Fatal adverse reactions within 30 days of the last dose occurred in 12% (19/158) of patients treated with COPIKTRA and in 4% (7/155) of patients treated with ofatumumab. Serious adverse reactions were reported in 73% (115/158) of patients treated with COPIKTRA and most often involved infection (38%; 60/158) and diarrhea or colitis (23%; 36/158). The most common adverse reactions with COPIKTRA (≥20% of patients) were diarrhea or colitis, neutropenia, pyrexia, upper respiratory tract infection, pneumonia, rash, fatigue, nausea, anemia and cough.

For specific information on the management of the adverse reactions above, please review Dose Modifications for Adverse Reactions within the full Prescribing Information.

DRUG INTERACTIONS

CYP3A Inducers: Coadministration with a strong CYP3A inducer may reduce COPIKTRA efficacy. Avoid coadministration with strong CYP3A4 inducers.

CYP3A Inhibitors: Coadministration with a strong CYP3A inhibitor may increase the risk of COPIKTRA toxicities. Reduce COPIKTRA dose to 15 mg BID when coadministered with a strong CYP3A4 inhibitor.

CYP3A Substrates: Coadministration of COPIKTRA with sensitive CYP3A4 substrates may increase the risk of toxicities of these drugs. Consider reducing the dose of the sensitive CYP3A4 substrate and monitor for signs of toxicities of the coadministered sensitive CYP3A substrate.

To report Adverse Reactions, contact FDA at 1-800-FDA-1088 (1-800-332-1088) or www.fda.gov/medwatch and Verastem Oncology at 1-877-7RXVSTM (1-877-779-8786).

Please see accompanying full Prescribing Information, including Boxed Warning.

About Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

Chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) are cancers that affect lymphocytes and are essentially the same disease, with the only difference being the location where the cancer primarily occurs. When most of the cancer cells are located in the bloodstream and the bone marrow, the disease is referred to as CLL, although the lymph nodes and spleen are often involved. When the cancer cells are located mostly in the lymph nodes, the disease is called SLL. The symptoms of CLL/SLL include a tender, swollen abdomen and feeling full even after eating only a small amount. Other symptoms can include fatigue, shortness of breath, anemia, bruising easily, night sweats, weight loss, and frequent infections. However, many patients with CLL/SLL will live for years without symptoms. There are approximately 200,000 patients in the US affected by CLL/SLL with nearly 20,000 new diagnoses this year alone. While there are therapies currently available, real-world data reveals that a significant number of patients either relapse following treatment, become refractory to current agents, or are unable to tolerate treatment, representing a significant medical need. The potential of additional oral agents, particularly as a monotherapy that can be used in the general community physician’s armamentarium, may hold significant value in the treatment of patients with CLL/SLL.

About COPIKTRA (duvelisib)

COPIKTRA is an oral inhibitor of phosphoinositide 3-kinase (PI3K), and the first approved dual inhibitor of PI3K-delta and PI3K-gamma, two enzymes known to help support the growth and survival of malignant B-cells. PI3K signaling may lead to the proliferation of malignant B-cells and is thought to play a role in the formation and maintenance of the supportive tumor microenvironment.1,2,3 COPIKTRA is indicated for the treatment of adult patients with relapsed or refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) after at least two prior therapies and relapsed or refractory follicular lymphoma (FL) after at least two prior systemic therapies. COPIKTRA is also being developed by Verastem Oncology for the treatment of peripheral T-cell lymphoma (PTCL), for which it has received Fast Track status, and is being investigated in combination with other agents through investigator-sponsored studies.4 For more information on COPIKTRA, please visit www.COPIKTRA.com. Information about duvelisib clinical trials can be found on www.clinicaltrials.gov.

On June 17, 2019 Medigene AG (FWB: MDG1, Prime Standard) reported that clinical data from the interim analysis of the ongoing Phase I / II clinical trial with Medigene’s DC vaccine for the treatment of acute myeloid leukemia was presented during the annual congress of the European Hematology Association (EHA) (Free EHA Whitepaper) taking place from 13 – 16 June in Amsterdam (Press release, MediGene, JUN 17, 2019, View Source [SID1234537117]).

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The poster presented was entitled "Interim Analysis of a WT-1 and PRAME ` Fast-DC´ vaccine shows safety as active immunotherapy for the prevention of AML relapse". The primary objectives of the study enrolling 20 AML patients are the safety and feasibility of this active immunotherapy with patient-derived DCs produced according to Medigene’s proprietary technology.

The data presented was generated over a period of one year of vaccination of all patients representing an interim dataset after half of the treatment period. Topline data of this interim analysis was already published on 19 December 2018, demonstrating a very good feasibility for manufacture of the vaccines as well as an excellent safety profile and encouraging data on overall survival and progression-free survival (Link to press release: View Source).

In addition, the data presented at EHA (Free EHA Whitepaper) included details about the mutational load status of patients who relapsed.

Clinical trial outline: A total of 20 subjects (median age 59, range 24 to 73) with AML (risk groups good, intermediate, poor: 13, 5, 2), in morphologic complete remission (CR) or complete remission with incomplete hematologic recovery (CRi) after induction or consolidation therapy, not eligible for allogeneic hematopoietic stem cell transplantation, were enrolled into this safety and feasibility Phase I/II trial, vaccinated and followed up for 12 months at the interim analysis timepoint. Subjects in this trial had AML that was positive for Wilms Tumor-1 (WT-1) antigen with or without positivity for Preferentially Expressed Antigen in Melanoma (PRAME). Vaccination with dendritic cells, presenting the antigens WT-1 and PRAME, was carried out monthly, with a higher frequency within the first 6 weeks. AML diagnoses had been established with a median of 9.8 months before the first vaccination (range 4.5 to 17.5 months), and the last chemotherapy infusion had been performed at a median of 6.9 months (range 2 to 14.8 months).

Interim results: The vaccinations were well tolerated with no serious adverse events (SAEs) related to the treatment. The most common adverse events (AEs) were injection site related, accounting for 35% of all AEs and mild in nature (Grade 1). The feasibility of the manufacture of the dendritic cell vaccine in these chemotherapy-pretreated subjects was already presented at AACR (Free AACR Whitepaper) in 2018 (Link to poster: View Source).

After a 12-months treatment period, the overall survival was 89% (18 of 20 patients, 95% confi-dence interval: 61 to 97%) and the progression free survival was 60% (12 of 20 patients, 95% confidence interval: 36 to 78%). Most relapses, 5 out of 8, occurred within the first 80 days after initiation of vaccination, suggesting a possible molecular relapse upon entering the study.

The presence of common mutations was analyzed in all patients via next generation sequencing and two of the five early relapses showed mutational load upon entering the study (IDH2 and DNMT3A mutation in one patient and multiple mutations in the second (RUNX1, KRAS, ETV6, BCOR, DNMT3A). Two of the later relapses also showed mutational load before vaccination, one patient with a KRAS and TET2 mutation and one patient with multiple mutations (RUNX1, IDH2, SRSF2 and DNMT3A).

Dr. Kai Pinkernell, CMO and CDO of Medigene AG, comments: " We are pleased that the interim results after one year of treatment show an excellent safety profile, a very good manufacturability and encouraging overall and progression free survival data. In addition, the mutational load analysis may also allow patients to be stratified in future clinical trials."

The completion of the ongoing trial is scheduled for the end of 2019, following a two-year treatment period.

About acute myeloid leukaemia (AML): Acute myeloid leukaemia is a malignant disease of the hematopoietic system, affecting mainly adults above 60 years of age. In Germany, about 3,600 cases are registered annually.

AML is caused by uncontrolled growth of dysfunctional hematopoietic precursor cells in the bone marrow. These cells prevent the generation of normal blood cells, causing a decrease in erythrocytes and platelets, for example. Typical symptoms of AML include anemia, fever, increased risk of infection, and bleeding. AML progresses rapidly and may be fatal within a few weeks or months, if untreated.

AML treatment is often started with intensive chemotherapy, followed by consolidation with or without allogeneic hematopoietic stem cell transplantation. Unfortunately, a significant proportion of patients suffer a relapse of the original disease. Depending on the biologic risk profile of the disease, age and co-morbidity the long-term survival is highly variable.

About Medigene’s DC vaccines: In addition to Medigene’s development focus on T cell-receptor modified T cells (TCR-Ts), the Company has developed a new generation of antigen-tailored dendritic cell (DC) vaccines.

Dendritic cells (DC) can take up antigens, process them and present peptides on their surface in a form that can induce antigen-specific T cells to mature and proliferate. In this way, T cells recognize and eliminate tumor cells which bear the same antigen peptide on their surface. Dendritic cells can also induce natural killer cells (NK cells) to attack tumor cells. The scientific team of Medigene has developed new, fast and efficient methods for generating autologous (patient-specific) mature dendritic cells which have the relevant characteristics to generate very strong T cell and NK cell immune responses. The dendritic cells can be loaded with various tumor antigens to treat different forms of cancer. Since an immune response builds up over the total time of administration of the DC vaccine, this form of therapy is particularly designed for patients who suffer from a tumor disease which has been reduced to such an extent by chemotherapy that the prevention of the recurrence of the tumor disease is the main goal.

On June 17, 2019 Celyad (Euronext Brussels and Paris, and Nasdaq: CYAD), a clinical-stage biopharmaceutical company focused on the development of CAR-T cell therapies, reported that updated clinical data for the CYAD-01 program in r/r AML and MDS was presented in a poster presentation session on Saturday, June 15 at the 24th Congress of the European Hematology Association (EHA) (Free EHA Whitepaper) in Amsterdam, Netherlands (Press release, Celyad, JUN 17, 2019, View Source [SID1234537116]).

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Dr. Frédéric Lehmann, VP of Clinical Development & Medical Affairs at Celyad, commented,"Our observations from the Phase 1 THINK clinical trial evaluating CYAD-01 without prior lymphodepletion in relapsed/refractory acute myeloid leukemia and myelodysplastic syndrome patients show the cell therapy is generally well tolerated. Encouragingly, this safety and tolerability profile was also demonstrated during the early stages of CYAD-01 treatment intensification where an increased systemic persistence of CAR-T cells is obtained after reduced interval dosing or in combination with preconditioning chemotherapy. As such, we continue to focus our efforts on increasing the aggressiveness of CYAD-01 to potentially deepen the breadth, frequency and duration of clinical responses in this refractory patient population."

THINK Phase 1 Trial in Hematological Malignancies Update

As of May 23 2019, preliminary anti-leukemic activity has been observed in six out of thirteen patients (46%) evaluable per protocol in the THINK Phase 1 trial with four out of thirteen patients (31%) exhibiting objective responses, including one out of the four patients experiencing a duration of response of over 90 days
Overall, multiple infusions of CYAD-01 without any prior preconditioning chemotherapy continues to show an encouraging tolerability profile with eight patients from over twenty treated experiencing grade 3/4 treatment-related adverse events (AEs). No neurotoxicity AEs have been observed in any patient receiving CYAD-01.
The denser schedule of infusions in the absence of any bridging or preconditioning chemotherapy without preconditioning chemotherapy evaluated in Cohort 10 showed that of three r/r AML or MDS patients evaluable, one patient experienced disease stabilization and two patients had disease progression following treatment with up to six doses of 1 billion cells of CYAD-01.
The denser dosing schedule was generally reported to be well-tolerated. Three patients of four patients evaluable for safety in Cohort 10 experienced grade 1/2 cytokine release syndrome (CRS), which showed rapid resolution following the appropriate treatment, including tocilizumab. One patient experienced a grade 4 infusion reaction, which was not considered to be a dose-limiting toxicity of the therapy
Overall, better time-averaged engraftment (area under the curve) was observed with a reduced interval dosing (Cohort 10) as compared to the equivalent dose of the THINK trial evaluating a cycle of three injections of CYAD-01 administered every two weeks.
Recruitment in Cohort 11 of the THINK trial evaluating the denser schedule of up to six infusions of three billion cells of CYAD-01 without preconditioning chemotherapy is ongoing and results are expected by the end of 2019.

DEPLETHINK Phase 1 Trial Update

The initial cohorts of the DEPLETHINK trial enrolled six r/r AML or MDS patients who received a single administration of a safety-precaution low-dose CYAD-01 (100 million cells per infusion) following preconditioning chemotherapy consisting of cyclophosphamide and fludarabine, or CyFlu, at two different time-intervals (three or seven days) between the preconditioning regimen and administration of CYAD-01.
As of May 23, 2019, three patients experienced grade 1/2 CRS, which showed rapid resolution following the appropriate treatment, including tocilizumab. One patient experienced a grade 4 infusion reaction, which was not considered to be a dose-limiting toxicity of the therapy, during the consolidation cycle without preconditioning.
Of the five patients evaluable per protocol, two patients experienced disease stabilization following treatment with CYAD-01.
Better time-averaged engraftment was observed after a single infusion of low-dose CYAD-01 with prior preconditioning compared to the dose-escalation segment of the THINK trial evaluating a cycle of three injections of CYAD-01.
Evaluation of higher dose-levels comparable to the Phase 1 THINK trial, including 300 million and 1 billion cells, are ongoing in the dose-escalation trial and preliminary results from these cohorts are expected by year-end 2019.
Background on THINK Phase 1 Trial

The THINK trial (NCT03018405) is an open-label, dose-escalation Phase 1 trial assessing the safety and clinical activity of multiple CYAD-01 administrations without prior preconditioning. The dose escalation segment of the trial evaluated three dose levels (300 million, 1 billion and 3 billion cells per infusion) of one cycle of three CYAD-01 administrations with two-week intervals.

In 2018, the THINK trial was amended to add two cohorts to assess a more frequent dosing schedule of CYAD-01 for the treatment of r/r AML. The cohorts will evaluate six injections of CYAD-01 without preconditioning over two months of administration. The first cycle includes three infusions of CYAD-01 separated by one-week intervals. The second cycle includes three infusions of CYAD-01 separated by two-week intervals. Patients will either receive 1 billion cells per infusion (Cohort 10) or 3 billion cells per infusion (Cohort 11). The primary endpoint of the trial is safety and secondary endpoints include clinical activity and pharmacokinetics.

Background on DEPLETHINK Phase 1 Trial

In October 2018, Celyad initiated the DEPLETHINK Phase 1 trial (NCT03466320). The open-label, dose-escalation trial will evaluate a single infusion of CYAD-01 following treatment with the standard preconditioning regimen of cyclophosphamide (300 mg/m²) and fludarabine (30 mg/m²), or CyFlu. The trial includes two different intervals between lymphodepletion and administration of CYAD-01. In addition, the trial will evaluate three dose levels of CYAD-01 including 100 million, 300 million and 1 billion cells per infusion, respectively. The primary endpoint of the trial is safety and secondary endpoints include clinical activity and pharmacokinetics.

On June 17, 2019 OncoSec Medical Incorporated (OncoSec) (NASDAQ: ONCS), a company developing intratumoral cancer immunotherapies, reported that it has initiated a research collaboration with Roswell Park Comprehensive Cancer Center to evaluate the use of Roswell Park’s intravital microscopy (IVM) and OncoSec’s proprietary plasmid, TAVOPLUS, in combination with the Company’s recently announced APOLLO electroporation generator in preclinical studies (Press release, OncoSec Medical, JUN 17, 2019, View Source [SID1234537115]). The collaboration will be led by Joseph Skitzki, MD, FACS, Associate Professor of Immunology, Associate Professor of Surgery and Chair of the Melanoma/Sarcoma Disease Site Research Group at Roswell Park.

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Intravital microscopy is a powerful tool that has provided unprecedented real time access to visualize and record molecular, cellular, anatomical function, providing insights into the immune activity within the tumor microenvironment. Data uncovered with the technique used in this collaboration will reveal a deeper understanding and possible new approaches to treatment with TAVOPLUS and APOLLO.

Dr. Skitzki’s laboratory plans to focus on IVM studies which provide an in vivo window to visualize and record movements of immune subsets in the periphery or, critically, in established tumors. This collaboration will investigate essential elements of lymphocyte trafficking driven by OncoSec’s enhanced therapeutic platform, including the new low-voltage APOLLO generator and TAVOPLUS plasmids. In addition to investigating the effects of chemokine gradients on rolling/adhesion of specific immune subsets, the laboratory will conduct time-course experiments to determine the associated kinetics of this therapy. The Skitzki laboratory will also perform translational studies to address whether neo-vascularization or changes to vascularization can be used to predict response.

"This research collaboration offers a significant opportunity to leverage cutting edge experimental techniques to gain a deeper mechanistic understanding of how OncoSec’s newest therapy drives lymphocyte trafficking into the tumor. We are particularly pleased to be working with Dr. Skitzki and with Roswell Park, a renowned research organization, and look forward to the critical data and related intellectual property that will emerge from this work," said Christopher G. Twitty, PhD, Chief Scientific Officer of OncoSec.

Dr. Skitzki specializes in the areas of melanoma and sarcoma, with a focus on intratumoral and regional therapies. His independent lab focuses on immunotherapies for melanoma and preclinical modeling of TAVOPLUS and APOLLO with the goal of clinical translation. Dr. Skitzki has authored or co-authored more than 50 journal publications, book chapters and abstracts.

"Based upon a significant body of clinical data, our lead oncology product candidate, TAVO, has distinguished itself by clearly showing an ability to induce T cell activation both within local (treated) and distant (untreated) tumor microenvironments, leading to the positive response data observed across several solid tumor types. The Roswell Park collaboration will enable OncoSec to further characterize the TAVOPLUS immune response and its impact on local and distant tumors, thereby imparting a fuller understanding of its clinical utility in the treatment of cancer," said Daniel J. O’Connor, President and Chief Executive Officer of OncoSec.

On June 17, 2019 Geron Corporation (Nasdaq: GERN) reported that an oral and a poster presentation of clinical data and analyses related to imetelstat, the Company’s first-in-class telomerase inhibitor, were made at the 24th Annual Congress of the European Hematology Association (EHA) (Free EHA Whitepaper) held in Amsterdam, the Netherlands on June 15, 2019 (Press release, Geron, JUN 17, 2019, View Source [SID1234537114]).

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Updated Efficacy and Safety Data from the Phase 2 Portion of IMerge

"The EHA (Free EHA Whitepaper) presentation for the Phase 2 portion of IMerge reported higher efficacy responses from prior reported data for both 8-week and 24-week RBC-TI rates, which highlight the meaningful and durable transfusion independence achievable with imetelstat treatment in heavily transfusion dependent lower risk MDS patients," said Aleksandra Rizo, M.D., Ph.D., Geron’s Chief Medical Officer. "These data provide further support for the initiation of the Phase 3 portion of the trial and Phase 3 start-up activities for IMerge are continuing with the goal of opening for screening and enrollment in August 2019."

Title: Treatment with Imetelstat Provides Durable Transfusion Independence (TI) in Heavily Transfused Non-del(5q) Lower Risk MDS (LR-MDS) Relapsed/Refractory (R/R) to Erythropoiesis Stimulating Agents (ESAs) (Abstract #S837)

This oral presentation described updated efficacy and safety data as of April 2019 from 38 imetelstat-treated patients in the Phase 2 portion of the IMerge clinical trial with a median follow-up of 15.7 months. All 38 patients represent a target patient population of transfusion dependent, non-del(5q) lower risk myelodysplastic syndromes (MDS) patients who are relapsed or refractory to ESAs and naïve to hypomethylating agent (HMA) and lenalidomide treatment.

The primary efficacy endpoint is the rate of red blood cell transfusion independence (RBC-TI) lasting at least eight weeks, or 8-week RBC-TI rate, which is defined as the proportion of patients achieving RBC-TI during any consecutive eight weeks since entry into the trial. Key secondary endpoints include the rate of RBC-TI lasting at least 24 weeks, or 24-week RBC-TI rate, and the rate of hematologic improvement-erythroid (HI-E), defined as a reduction of at least four units of RBC transfusions over eight weeks compared with the prior RBC transfusion burden or a rise in hemoglobin of at least 1.5 g/dL above pretreatment level for at least eight weeks.

Efficacy Summary (n=38):

42% (16/38) of patients achieved ≥8-week RBC-TI
29% (11/38) of patients achieved ≥24-week RBC-TI
Median duration of TI was 85.9 weeks (range: 8.0-140.9)
68% (26/38) of patients achieved HI-E, or improvement in red blood cell count, as measured by either transfusion reduction or a rise in hemoglobin:
° All 26 patients had a reduction of at least four RBC units over eight weeks compared with prior transfusion burden
° 12 of 26 patients had a hemoglobin increase of at least 1.5 g/dL lasting at least eight weeks
Mean relative reduction in transfusion burden from baseline was 68%
Additional data were presented showing that transfusion independence was observed across different clinical subgroups, as well as in patients with intermediate or poor cytogenetic risk.

Safety Summary:

No new safety signals were identified. Reversible cytopenias were the most frequent adverse events.
The slide presentation is available on Geron’s website at www.geron.com/r-d/publications.

Statistical Analyses of Median Overall Survival in IMbark Compared to Real World Data

"The EHA (Free EHA Whitepaper) poster presentation reported the results of statistical analyses in which the months of median overall survival for imetelstat-treated relapsed/refractory MF patients in IMbark was calculated to be more than double that for closely matched patients treated with best available therapy using real-world data," said John A. Scarlett, M.D., Geron’s Chairman and Chief Executive Officer. "The outcomes of these analyses were consistent across two different approaches for propensity score analysis and additional sensitivity analyses, underscoring the robustness of the statistical methodologies applied."

Abstract Title: Favorable Overall Survival of Imetelstat-Treated Relapsed/Refractory Myelofibrosis Patients Compared with Closely Matched Real World Data (Abstract #PS1456)

This poster presentation provided a new analysis of overall survival (OS) in relapsed/refractory MF patients treated with imetelstat 9.4 mg/kg in the IMbark Phase 2 clinical trial, compared to OS calculated from real world data (RWD) collected at the Moffitt Cancer Center for patients who had discontinued treatment from ruxolitinib, a JAK inhibitor, and who were subsequently treated with best available therapy (BAT). To make a comparison between the IMbark data and RWD, a cohort from the real-world dataset was identified that closely matched the IMbark patients, using guidelines for inclusion and exclusion criteria as defined in the IMbark clinical protocol, such as platelet count and spleen size.

To mimic the effect of randomization and improve comparability between the IMerge and RWD populations, two different propensity score approaches were used to balance these two populations with respect to baseline covariates and prognostic factors that could have impacted OS outcomes. The calculations from both propensity score approaches resulted in a median OS of 30.7 months for the imetelstat-treated patients from IMbark, which is more than double the median OS of 12.0 months using RWD for patients treated with BAT. The analysis also indicated a 65-67% lower risk of death for the imetelstat-treated patients vs. BAT-treated patients. A sensitivity analysis assessing the impact on OS of subsequent hematopoietic stem cell transplantation showed no substantial differences in median OS calculated for either the imetelstat-treated or BAT-treated patients. The poster presentation concluded that although there are limitations of such comparative analyses between RWD and clinical trial data, favorable OS of imetelstat treatment in this very poor-prognosis patient population warrants further evaluation.

The poster is available at www.geron.com/r-d/publications.

Post-EHA Event with Key Opinion Leaders

On June 25, 2019, Geron will be hosting a webcasted event with authors from each respective data presentation from the EHA (Free EHA Whitepaper) Annual Congress who will reprise the presentations from EHA (Free EHA Whitepaper). Information regarding access to the webcast is available at www.geron.com/investors/events.

Current Ongoing Clinical Trials of Imetelstat

Patients currently enrolled in ongoing imetelstat clinical trials continue to be supported through the respective trial protocols, including treatment and follow-up.

Phase 2 Portion of IMerge

IMerge is a two-part Phase 2/3 clinical trial of imetelstat in lower risk MDS. The first part of IMerge was designed as a Phase 2, open label, single arm study to assess the efficacy and safety of imetelstat. The primary efficacy endpoint is 8-week RBC-TI rate, which is defined as the proportion of patients achieving red blood cell transfusion independence during any consecutive eight weeks since entry into the trial.

Key secondary endpoints include the rate of RBC-TI lasting at least 24 weeks, or 24-week RBC-TI rate, and the rate of hematologic improvement-erythroid (HI-E), defined as a reduction of at least four units of RBC transfusions over eight weeks compared with the prior RBC transfusion burden or a rise in hemoglobin of at least 1.5 g/dL above pretreatment level for at least eight weeks. To be eligible for the Phase 2 or Phase 3 portion of IMerge, patients are required to be transfusion dependent, defined as requiring at least four units of packed RBCs over an eight-week period during the 16 weeks before entry into the trial. The Phase 2 portion of IMerge is closed to new patient enrollment.

IMbark

IMbark was designed as a Phase 2 clinical trial to evaluate two starting dose levels of imetelstat (either 4.7 mg/kg or 9.4 mg/kg administered by intravenous infusion every three weeks) in patients with Intermediate-2 or High-risk MF who have relapsed after or are refractory to prior treatment with a janus kinase (JAK) inhibitor. The co-primary efficacy endpoints for the trial are spleen response rate and symptom response rate. Key secondary endpoints are safety and overall survival (OS). IMbark is closed to new patient enrollment.

About Imetelstat

Imetelstat is a novel, first-in-class telomerase inhibitor exclusively owned by Geron and being developed in hematologic myeloid malignancies. Early clinical data suggest imetelstat may have disease-modifying activity through the suppression of malignant progenitor cell clone proliferation, which allows potential recovery of normal hematopoiesis. Ongoing clinical studies of imetelstat consists of a Phase 2/3 trial, called IMerge, in lower risk myelodysplastic syndromes (MDS) and a Phase 2 trial, called IMbark, in Intermediate-2 or High-risk myelofibrosis. Imetelstat received Fast Track designation from the United States Food and Drug Administration for the treatment of patients with transfusion-dependent anemia due to lower risk MDS who are non-del(5q) and refractory or resistant to an erythroid stimulating agent.