On June 4, 2018 Ayala Pharmaceuticals, a clinical stage precision oncology biopharmaceutical company dedicated to developing novel targeted therapies for genomically defined cancers in patient populations with high unmet medical needs, reported results from the Phase 1b study of AL101 (formerly BMS-906024), a gamma secretase inhibitor that potently inhibits signaling downstream of Notch receptors (1, 2, 3 and 4) (Press release, Ayala Pharmaceuticals, JUN 4, 2018, View Source [SID1234527161]). These data were accepted for a poster presentation titled, "A phase I study of AL101, a pan-Notch inhibitor, in patients with locally advanced or metastatic solid tumors," at the 2018 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting in Chicago. The poster was selected for a discussion session that will take place on Monday, June 4, 2018, from 3:00 p.m.-4:15 p.m. in Hall A, Room S406, McCormick Place.

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The primary objective of the study was to assess the safety and tolerability of multiple IV doses of AL101, and to establish the recommended Phase 2 dose. Secondary objectives were to assess the pharmacokinetics (PK) and pharmacodynamics (PD) of AL101 and its equally active metabolite after the first IV dose and after repeated doses. All study objectives were met.

AL101 is a best-in-class gamma secretase inhibitor that has demonstrated potent and selective inhibition downstream of all four Notch receptors in preclinical models. Based on these encouraging findings, a Phase 1 study was designed in advanced solid tumors to evaluate safety and tolerability as well as PK and PD of the compound.

Ninety-four patients were enrolled in the study and treated with one of two alternative regimens: Arm A (QW, n=83) and Arm B (Q2W, n=11) using a 3+3 design, with expansion at the maximum tolerated dose (MTD). Tumor types included adenoid cystic carcinoma (ACC), triple negative breast cancer (TNBC), non-small cell lung cancer (NSCLC) and selected other tumors with reported Notch activation. The defining dose-limiting toxicity (DLT) period was four weeks (4 doses QW or 2 doses Q2W). PD biomarkers of Notch activity, including HES1 mRNA, were evaluated in serial whole blood.

A MTD of 4 mg QW was established in the escalation phase and used in the expansion phase. The safety profile was consistent with that on target effects of Notch inhibition. The majority of adverse effects were low grade and manageable with protocol guidelines. Grade 3/4 events reported in >15% (all doses, Arm A) included: diarrhea 17 (20%), hypophosphatemia 31(37%), nausea 1 (1%), vomiting 4 (5%), hypokalemia 6 (7%).

Seven DLTs were reported in Arm A: four in patients receiving 6 mg, (Grade 3 vomiting, Grade 3 diarrhea, Grade 3 diarrhea/colonic ulcerations, Grade 3 diarrhea/Grade 4 dehydration) and in three patients receiving 8.4 mg (Recurrent Grade 3 infusion reaction, Grade 3 vomiting, Grade 5 hepatic failure). There were no DLTs in three DLT-evaluable patients at 6 mg QW during escalation, and once 8.4 mg QW was deemed above the MTD, 11 additional patients were enrolled at 6 mg (10 were DLT evaluable). There were no DLTs in seven DLT-evaluable patients receiving 4 mg QW.

Weekly dosing of AL101 led to continuous Notch inhibition as measured by HES 1 transcription at doses 4 mg QW and above. Clinical activity was demonstrated across different solid tumor types at the MTD as defined by RECIST v1.1: one complete response was observed in a patient with a gastroesophageal junction adenocarcinoma with two missense and one splice-site mutation in Notch 1. One partial response was observed in a patient with a desmoid tumor, and one PR was observed in a patient with an ACC, with mutated Notch 1.

"Ayala is dedicated to precision oncology, bringing forward targeted therapies for cancer patients with high unmet needs," said Roni Mamluk, Ph.D., Chief Executive Officer at Ayala Pharmaceuticals. "As we continue our clinical development plans for Ayala’s Phase 2 study in the second half of this year, we are particularly encouraged by AL101’s clinical activity seen to date and look forward to initiating trials in our lead indication, ACC, in patients with activated Notch pathway, an indication with no approved treatment and patients in need for a therapy."

On June 4, 2018 Tarveda Therapeutics, Inc., a clinical stage biopharmaceutical company discovering and developing Pentarins as a new class of potent and selective medicines to treat a wide range of cancers, reported Phase 1 results that were presented at the American Society for Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting from an ongoing Phase 1/2a study of PEN-221 in patients with somatostatin receptor 2 (SSTR2)-expressing neuroendocrine tumors (NET) or small cell lung cancer (SCLC) (Press release, Tarveda Therapeutics, JUN 4, 2018, View Source [SID1234527160]). The results presented had a data cutoff date of February 23, 2018. As of April 11, 2018, four patients remained on study.

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"PEN-221, our lead Pentarin miniature drug conjugate, is designed to rapidly penetrate deep into solid tumors where it is highly selective for the somatostatin receptor 2 and accumulates its potent DM1 payload," said Richard Wooster, Ph.D., President of Research and Development and Chief Scientific Officer at Tarveda. "Based on the safety results and encouraging signs of antitumor activity seen in our Phase 1 dose escalation and safety study for PEN-221, we have initiated the Phase 2a portion of our Phase 1/2a trial of PEN-221 to explore its potential in treating patients with gastrointestinal midgut and pancreatic neuroendocrine tumors as well as small cell lung cancer."

The Phase 1 portion of the study was designed as a dose escalating study to assess safety, tolerability, pharmacokinetics, and preliminary antitumor activity of PEN-221 in patients with SSTR2-expressing advanced neuroendocrine or small cell lung cancers. The results show that PEN-221 appears to be well-tolerated with evidence of antitumor activity seen in multiple patients. The maximum tolerated dose (MTD) and the recommended Phase 2 dose (RP2D) was established as 18mg and will be further evaluated in the Phase 2a portion of the study.

"There is a very real need for new treatment options for patients living with neuroendocrine tumors and small cell lung cancer," said Melissa Johnson, M.D., Associate Director, Lung Cancer Research Program at Sarah Cannon Research Institute. "PEN-221, an SSTR2 directed drug conjugate linked to a DM1 cytotoxic payload, is an exciting and novel approach to treating patients with SSTR2 expressing tumors identified using biomarker imaging agents OctreoScan or Gallium-68 DOTATATE PET. PEN-221 was well tolerated by patients in this clinical trial. In addition, the encouraging signals of antitumor activity and prolonged stable disease further supports continuation of the study of PEN-221 in the Phase 2a trial."

Phase 1 Trial Design

PEN-221 was administered as a one-hour, intravenous infusion once every three weeks to escalating cohorts of two to six patients with SSTR2 expressing advanced solid tumors including advanced gastroenteropancreatic, lung, thymus or other neuroendocrine tumors or small cell lung cancers or large cell neuroendocrine tumors of the lung. Safety was assessed by vital sign measurements, physical examinations, neurological examinations, ECOG performance status, documentation of adverse events, clinical laboratory tests, and electrocardiography. Disease response was assessed by duration of response and standard RECIST criteria.

Safety Data

A safety analysis of all 23 patients demonstrated that PEN-221 was well-tolerated with no dose limiting toxicities up to 18mg. Two of three patients administered 25mg of PEN-221 experienced dose limiting toxicities that rapidly and fully resolved following treatment discontinuation.

The majority of treatment-related/treatment-emergent adverse events were mild (Grade 1) to moderate (Grade 2) with the most common being fatigue (48%), nausea (48%), diarrhea (44%), and peripheral neuropathy (26%). There were single reports of Grade 3 peripheral neuropathy, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) increase and constipation at the 25mg dose. One patient at the 25mg dose experienced a Grade 3 drug induced liver injury.

The Maximum Tolerated Dose and Recommended Phase 2 Dose of PEN-221 is 18mg administered once every 3 weeks.

Efficacy data

There was preliminary evidence of antitumor activity:

Among 15 NET patients who were evaluable for response, 11 had stable disease (SD) at 9 weeks, of whom 8 were sustained for 18-45 weeks, including 2 ongoing patients with SD for 44 and 45 weeks at the time of this data review.
Target lesion shrinkage leading to minor responses at the time of this data review were observed in 3/7 patients who had either a GI or pancreatic NET (dose range 8-18 mg).
The only SCLC patient had SD for 12 weeks.
As of April 11, 2018, four patients remained in the Phase 1 portion of the study with stable disease of 5, 7, 12, 14 months respectively.

About PEN-221

PEN-221 is a miniature drug conjugate consisting of a peptide ligand, that is highly selective in targeting SSTR2, joined through a cleavable linker to the potent cytotoxic payload DM1. SSTR2 is overexpressed on the cell surface of a range of solid tumors including neuroendocrine tumors and small cell lung cancers. In non-clinical experiments, PEN-221 binds with high affinity and selectivity to SSTR2. On binding, PEN-221 triggers SSTR2 internalization resulting in the accumulation of the DM1 payload in tumor cells followed by cell cycle arrest and apoptosis.

PEN-221 is being evaluated in Phase 2a expansion cohorts enrolling patients with midgut neuroendocrine tumors, pancreatic neuroendocrine tumors, and small cell lung cancer (ClinicalTrials.gov Identifier: NCT02936323).

About Pentarins
Tarveda is developing Pentarins, potent and selective miniature drug conjugates with high affinity for specific cell surface and intracellular targets. Pentarins are engineered to bind to their tumor cell targets and provide sustained release of their potent therapeutic payloads deep into solid tumor tissue. Comprised of a targeting ligand conjugated to a potent cancer cell killing agent through a tuned chemical linker, Pentarins are designed to overcome the deficits of both larger antibody drug conjugates and small molecules that limit their therapeutic effectiveness against solid tumors. Together, the components of Tarveda’s Pentarins have distinct, yet synergistic, anticancer attributes: the small size of Pentarins allows for rapid and deep penetration into the tumor tissue, the ligand’s targeting ability allows for specific binding and retention in tumor cells, and the chemical linker is tuned to optimize the release of the potent, cell killing payload inside the cancer cells for efficacy.

On June 1, 2018 Acceleron Pharma Inc. (Nasdaq:XLRN), a leading biopharmaceutical company in the discovery and development of TGF-beta therapeutics to treat serious and rare diseases, reported updated results from the Phase 2 trials of luspatercept in patients with lower-risk myelodysplastic syndromes (MDS) at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) 2018 Annual Meeting in Chicago (Press release, Acceleron Pharma, JUN 4, 2018, View Source [SID1234527159]). Luspatercept is being developed as part of a global collaboration between Acceleron and Celgene.

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"The ongoing Phase 2 trials continue to provide important insights into luspatercept’s potential to deliver long-term benefit to thousands of patients with lower-risk MDS," said Habib Dable, President and Chief Executive Officer of Acceleron. "With multiple patients on treatment for more than three years, we are increasingly confident in luspatercept’s novel mechanism as an erythroid maturation agent to address a significant unmet medical need in lower-risk MDS. We look forward to sharing top-line results from the MEDALIST Phase 3 trial over the next few months."

Patients with MDS suffer from insufficient production of red blood cells, resulting in chronic anemia that can lead to debilitating fatigue, diminished quality of life and increased mortality. Because MDS-related chronic anemia often fails to respond to unapproved therapies which include erythropoiesis-stimulating agents, many patients require frequent red blood cell transfusions.

Phase 2 Results

A total of 101 patients with lower-risk MDS have been treated with luspatercept (dose levels ≥ 0.75 mg/kg) in the Phase 2 trials.

55% (55 of 101 patients) achieved a clinically meaningful erythroid improvement (IWG HI-E criteria).
44% (30 of 68 patients) with a red blood cell (RBC) transfusion burden at baseline achieved RBC transfusion independence (RBC-TI) for at least 8 weeks.
The mean duration of treatment for RBC-TI responders was 18.3 months (n=30, ongoing).
Multiple patients continue on treatment through 40 months, and continue to sustain a clinically meaningful increase in hemoglobin and reduction in transfusion burden.
Phase 2 Safety Summary

The majority of adverse events (AEs) were Grade 1 or 2. Grade 3 non-serious AEs possibly related to study drug were ascites, blood bilirubin increase, bone pain, hypertension, mucosal inflammation, platelet count increase, and transformation to AML (previously reported as a blast cell count increase). The Grade 3 non-serious AEs occurred in one patient each, with the exception of hypertension in 2 patients.

Serious AEs (SAEs) possibly related to study drug were general physical health deterioration, muscular weakness, musculoskeletal pain, and myalgia. The four SAEs occurred in three individual patients.

The ASCO (Free ASCO Whitepaper) MDS poster presentation is available under the Science page of the Company’s website at www.acceleronpharma.com.

Luspatercept is an investigational product that is not approved for any use in any country.

About the Ongoing MDS Phase 2 Trials

Data from two Phase 2 trials were presented at the 2018 ASCO (Free ASCO Whitepaper) Annual Meeting: the base study in which patients with lower-risk MDS received treatment with luspatercept for three months and the long-term extension study in which patients who completed the base study may receive treatment with luspatercept for up to an additional five years.

About Luspatercept

Luspatercept is a first-in-class erythroid maturation agent (EMA) that regulates late-stage red blood cell maturation. Acceleron and Celgene are jointly developing luspatercept as part of a global collaboration. Phase 3 clinical trials are underway to evaluate the safety and efficacy of luspatercept in patients with MDS (the MEDALIST trial) and in patients with beta-thalassemia (the BELIEVE trial). A Phase 3 trial is being planned in first-line, lower-risk, MDS patients (the COMMANDS trial). The BEYOND Phase 2 trial in non-transfusion-dependent beta-thalassemia and a Phase 2 trial in myelofibrosis are ongoing. For more information, please visit www.clinicaltrials.gov.

On June 4, 2018 MiNA Therapeutics, the pioneer in RNA activation (RNAa) therapeutics, reported preliminary results from its ongoing Phase I study of small activating RNA (saRNA) candidate MTL-CEBPA in advanced liver cancer (Press release, MiNA Therapeutics, JUN 4, 2018, View Source [SID1234527158]). In the study, MTL-CEBPA was generally well tolerated in patients with both healthy and impaired liver function and provided evidence of anti-tumour activity. MTL-CEBPA was also found to mediate RNAa activity in white blood cells. The data are being presented at the 2018 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting in a poster titled "Preliminary results of a first-in-human, first-in-class phase I study of MTL-CEBPA, a small activating RNA (saRNA) targeting the transcription factor C/EBP-a in patients with advanced liver cancer" in the Developmental Therapeutics – Clinical Pharmacology and Experimental Therapeutics poster discussion session being held on Monday June 4, 2018 from 3:00pm to 4:15pm CDT.

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"Despite recent advances in treatment options, liver cancer remains a significant unmet medical need with numerous hurdles for therapeutic intervention. New treatment options are desperately needed, in particular for those patients with impaired liver function," said Dr. Debashis Sarker, Principal Investigator at the National Institute for Health Research Clinical Research Facility at Guy’s and St Thomas’ and King’s College London, and chief investigator of the study. "These preliminary safety data and the evidence of anti-tumour activity are very promising and I look forward to evaluating MTL-CEBPA in the dose expansion part of this Phase I clinical trial."

"We are extremely pleased with the preliminary results of this first-in-human study which include safety and tolerability of MTL-CEBPA, as well as evidence of anti-tumour activity in this very advanced, heavily pre-treated cancer patient population. In particular we have seen many patients achieve stable disease or better, including a patient with advanced hepatocellular carcinoma who has achieved over 70% tumour regression and has continued on the study for over one and half years," said Robert Habib, CEO of MiNA Therapeutics. "Additionally, analysis of patient blood samples has demonstrated upregulation of target CEBPA mRNA in white blood cells, representing a significant milestone in the development of saRNA medicines and for our platform."

MTL-CEBPA was evaluated in the dose escalation part of a Phase I clinical trial in patients with advanced liver cancer. As of the data cut-off date of March 31, 2018, 23 patients had been treated once weekly at six dose levels (ranging from 28 mg/m2 to 160 mg/m2) and 5 patients had been treated twice weekly at 70 mg/m2.

MTL-CEBPA was well tolerated in patients at all doses and no Maximum Tolerated Dose was identified. The large majority of adverse events (AEs) reported by investigators were mild to moderate in severity. 12 (43%) patients experienced AEs no higher than Grade 2. AEs of Grade 3 or higher included hyperbilirubinaemia (11%), elevated GGT (11%), hypophosphataemia (11%), anaemia (7%) and hypertension (7%). Only 3 (11%) patients discontinued treatment with MTL-CEBPA due to possible drug-related toxicities including acute coronary syndrome, hyperbilirubinaemia, and elevated GGT.

Pharmacokinetic data from this study showed that Cmax (peak plasma concentration of drug) and AUC (area under the curve) were dose proportional with no evidence of drug accumulation.

CEBPA gene expression was analysed in white blood cells of 10 patients across multiple dose levels and timepoints. The level of CEBPA gene expression was significantly higher on treatment than at baseline, supporting target engagement of MTL-CEBPA. Consistent with up-regulation of CEBPA, which has a role in myeloid differentiation, significant and repeated increases in neutrophils were observed after dosing MTL-CEBPA.

Enrollment in the dose escalation part of the Phase I clinical trial has been completed. Enrollment is starting for in the dose expansion part of the Phase I clinical trial in multiple sites in the United Kingdom and Asia. For more information, please contact us at [email protected].

About MTL-CEBPA
MTL-CEBPA consists of a double stranded RNA formulated into a SMARTICLES liposomal nanoparticle and is designed to activate the CEBPA gene. By restoring CEBPA expression to normal levels, MTL-CEBPA has been demonstrated to attenuate or reverse liver disease in a range of pre-clinical studies including models of liver cancer, liver cirrhosis, non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH). MTL-CEBPA is currently under evaluation in OUTREACH, a first-in-human Phase I clinical study in patients with severe liver cancer. The multi-centre Phase I study is assessing the safety and tolerability of MTL-CEBPA in patients with advanced liver cancer who are ineligible or resistant to standard therapies. To learn more about the OUTREACH clinical study, please visit our listing at clinicaltrials.gov

On June 4, 2018 Verastem, Inc. (NASDAQ:VSTM) (Verastem Oncology or the Company), a biopharmaceutical company focused on developing and commercializing medicines to improve the survival and quality of life of cancer patients, reported the presentation of five posters highlighting data for its two lead drug candidates, duvelisib and defactinib, at the 54th Annual Meeting of the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) being held June 1-5, 2018 in Chicago (Press release, Verastem, JUN 4, 2018, View Source;p=RssLanding&cat=news&id=2353079 [SID1234527157]).

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Duvelisib is a first-in-class oral dual inhibitor of phosphoinositide 3-kinase (PI3K)-delta and PI3K-gamma that is currently being developed for the treatment of relapsed or refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and follicular lymphoma (FL). In addition, duvelisib is being studied in other hematologic malignancies including peripheral T cell lymphoma (PTCL). In April, the U.S. Food and Drug Administration (FDA) accepted with Priority Review Verastem Oncology’s New Drug Application for duvelisib, which has an FDA target action date of October 5, 2018. Defactinib is an oral small molecule inhibitor of focal adhesion kinase (FAK) and is currently being evaluated in combination with immunotherapeutic agents for the treatment of various cancers including pancreatic, ovarian and non-small cell lung cancer, and mesothelioma.

"The DUO crossover extension data reported at ASCO (Free ASCO Whitepaper) this year build upon the previously reported positive Phase 3 DUO study results and further support duvelisib’s potential as an oral treatment option for patients with relapsed or refractory CLL/SLL," said Diep Le, MD, PhD, Chief Medical Officer of Verastem Oncology. "Post-crossover, oral duvelisib monotherapy demonstrated robust clinical activity with a 73% overall response rate (ORR) and a 15-month median PFS in the 89 patients that had previously received ofatumumab on DUO and subsequently progressed . Duvelisib monotherapy also demonstrated a manageable safety profile, with results from this study consistent with the well-characterized safety profile of duvelisib monotherapy in previous studies. It is encouraging to see such a robust response to duvelisib monotherapy, similar to response observed in the parent DUO study, in patients that had failed an additional line of therapy and needed a new treatment option."

Jonathan Pachter, PhD, Chief Scientific Officer of Verastem Oncology, commented, "The presented research by Drs. Casulo and Weaver continues to provide important evidence that the dual PI3K-delta/PI3K-gamma inhibitory activity of duvelisib results in beneficial anti-tumor effects on both the cancer cells and their supportive tumor microenvironment (TME) which has the potential to enhance clinical efficacy and improve outcomes for patients battling CLL/SLL and FL."

Dr. Le added, "Dr. Andrea Wang-Gillam presented initial results from an ongoing Phase 1 study evaluating our lead FAK inhibitor defactinib in combination with pembrolizumab and gemcitabine in patients with advanced pancreatic cancer. The triplet appears to be well tolerated, the recommended Phase 2 dose has been established, and the expansion phase of the study is ongoing. In addition, promising signs of clinical activity have been observed with 3 pancreatic cancer patients treated beyond 250 days, including a confirmed partial response and the other 2 patients with stable disease. All 3 of these patients have also shown meaningful reductions (57-96%) in the pancreatic cancer marker CA19-9. Analysis of paired biopsies have also shown that this treatment induced desirable biomarker changes including increased proliferating CD8+ T cells and reduced immunosuppressive Tregs and macrophages. Treatment of pancreatic cancer represents a very important unmet need for patients, and these initial results are certainly encouraging."

Details for the ASCO (Free ASCO Whitepaper) 2018 presentations are as follows:

Duvelisib

Title: The efficacy of duvelisib monotherapy following disease progression on ofatumumab monotherapy in patients with relapsed/refractory CLL or SLL in the DUO crossover extension study
Lead author: Dr. Bryone Kuss, Flinders Medical Centre
Abstract #: 7533
Summary: In the previously reported Phase 3 DUO study oral duvelisib monotherapy achieved a statistically significant improvement in median progression-free survival (mPFS) compared to ofatumumab in patients with relapsed or refractory CLL/ SLL (13.3 months versus 9.9 months, respectively; HR=0.52; p<0.0001), along with a manageable safety profile (Flinn, ASH (Free ASH Whitepaper) 2017). The results reported here are from the open-label, DUO crossover extension study where patients with confirmed progressive disease (PD) following treatment with ofatumumab in DUO were given the option to receive treatment with duvelisib. Duvelisib 25mg BID was administered until PD, intolerance, death, or study withdrawal and responses were determined by investigators using modified IWCLL/IWG criteria.

Among the 89 evaluable patients (median three prior therapies (range 2-8), oral duvelisib monotherapy achieved a 73% overall response rate (ORR; 95% CI: 64, 82; 5% complete response with incomplete marrow recovery (CRis), 68% partial responses [PRs]) in the extension study. While on ofatumamab in the DUO study, these 89 patients had a 28% ORR (95% CI: 19, 37; 1% complete response (CR), 27% PRs). The mPFS for duvelisib in the extension study was 15 months (95% CI: 10, 17). While on ofatumamab in the DUO study, these 89 patients had a mPFS of 9 months (95% CI: 9, 11), per investigator’s assessment. Notably, 83% of patients in the duvelisib arm post-crossover had >50% reductions in the size of their target nodal lesions. These same 89 patients had 27% reductions in the size of their target nodal lesions in the DUO ofatumumab arm. Median exposure to duvelisib in the extension study was 32 weeks. The safety profile of duvelisib monotherapy was manageable and consistent with what was observed in the Phase 3 DUO study. The most common Grade ≥3 treatment-emergent adverse events were neutropenia (22%), diarrhea (17%), colitis (9%), pneumonia (9%), rash (5%) and pyrexia (4%). These data build upon the previously reported positive DUO results and further support oral duvelisib monotherapy as an effective oral treatment option for patients with relapsed or refractory CLL/SLL.

A copy of the poster presentation will be available here.

Title: The effect of duvelisib, a dual inhibitor of PI3K-δ,γ, on components of the tumor microenvironment in previously untreated follicular lymphoma
Lead author: Dr. Carla Casulo, University of Rochester, Wilmot Cancer Center
Abstract #: 7579
Summary: In previously reported data from the CONTEMPO trial, treatment-naive FL patients treated with duvelisib in combination with rituxumab had an ORR of 93% (36% CRR), and an ORR of 89% (41% CRR) was observed for patients treated with duvelisib in combination with obinutuzumab. In this study, blood samples from healthy volunteers and FL patients treated in the CONTEMPO study, both pre- and post-duvelisib treatment, were analyzed. Ex vivo and in vitro PI3K-γ assays and PI3K-δ assays, with PI3K-δ-selective (idelalisib, TGR-1202, IPI-3063) and PI3K-γ-selective (IPI-549) inhibitors were compared.

Duvelisib and idelalisib potently inhibited LPS-induced human monocytes via PI3K-δ, compared with the PI3K-γ selective IPI-549. For TGR-1202, the IC50 was below the recommended Phase 2 dose (RP2D) clinical exposure. Duvelisib and IPI-549 potently inhibited PI3K-γ dependent fMLP-stimulated human monocytes compared to idelalisib and TGR-1202. In FL patients treated with duvelisib, these PI3K-γ and PI3K-δ selective assays were inhibited 1-4 hours post treatment. Consistent with a PI3K-γ mechanism, both duvelisib and IPI-549 inhibited macrophage polarization to M2, reduced CXCL12-induced macrophage migration, and blocked CXCL12-induced T cell migration, which was not observed with PI3K-δ inhibitor IPI-3063. Collectively, these results support the thesis that duvelisib disrupts PI3K- δ,γ function in FL patients inhibiting the TME through cancer-supportive macrophages and T cells.

A copy of the poster presentation will be available here.

Title: The PRIMO study: A phase 2 study of duvelisib efficacy and safety in patients with relapsed or refractory peripheral t-cell lymphoma (PTCL)
Lead author: Dr. Steven Horwitz, Memorial Sloan Kettering Cancer Center
Abstract #: TPS7590
Summary: This poster describes the PRIMO study, a Phase 2 open-label clinical trial evaluating duvelisib monotherapy in adult patients with PTCL, one of the most aggressive forms of non-Hodgkin lymphoma (NHL). The study employs a dose optimization phase (DOP) and an Expansion Phase (EP). The primary objectives are to identify the optimal dose of duvelisib in PTCL and examine the efficacy, safety, and tolerability of duvelisib at the optimal dose. The study is expected to enroll up to 120 patients with histologically confirmed PTCL subtypes of PTCL-NOS, angioimmunoblastic TCL, anaplastic large cell lymphoma, and natural-killer TCL. Disease responses will be measured by PET-CT scanning as assessed by an independent review committee per IWG criteria. The primary endpoint is ORR (CR + PR) in all patients receiving the optimal dose for at least 1 cycle in either phase. Secondary endpoints include safety, duration of response, and PFS. This study is open for enrollment. Duvelisib has been granted Fast Track designation by the U.S. Food and Drug Administration (FDA) for the treatment of patients with PTCL who have received at least one prior therapy.

A copy of the poster presentation will be available here.

Title: Duvelisib inhibition of chemokines in patients with CLL (DUO study) and iNHL (DYNAMO study)
Lead author: Dr. David Weaver, Verastem Oncology
Abstract #: 12048
Summary: PI3K-δ inhibition directly targets proliferation and survival of malignant leukemia and lymphoma cells, while PI3K-γ inhibition modulates the TME through key support cells, including tumor-associated macrophages, nurse-like stroma and T cells, and via soluble factors stimulating tumor growth, survival and migration. Serum samples from patients in the Phase 3 DUO study in relapsed/refractory CLL/SLL and the Phase 2 DYNAMO study in relapsed/refractory indolent NHL were collected at baseline and at C2D1 and used for correlative studies of 24 chemokines, cytokines and serum factors.

In serum samples from the DUO study, CCL1, CCL17, CXCL9, CXCL10, CXCL11, and IL-10 were reduced in patients treated with duvelisib (median 43.8%) but not in those treated with ofatumumab (p≤0.0009). Eight chemokines were reduced in both treatment arms, but the level of reduction was significantly greater for duvelisib-treated patients (median 64.6% for duvelisib versus 26.8% for ofatumumab [p≤0.001]). Many of the chemokines inhibited following duvelisib treatment are associated with the TME, including TNFα, IL-10, IL2Rα, IL12P40, CCL1, CCL17, CCL19, CXCL9, CXCL10, CXCL11, and CXCL13. In serum samples from the DYNAMO study, 13 corresponding chemokines were also inhibited (p≤0.008), including TME factors. Reductions occurred rapidly (by C2D1) in both studies. In DUO, there was a correlation between duration of response and reduction of the following chemokines: CCL17, CXCL11, IL-6, TRAIL, VEGF-D and TPO. These data support the hypothesis that treatment with duvelisib results in significant reduction of chemokines potentially derived from the tumor cells and TME and that further investigation of the effects of duvelisib on TME pharmacodynamic markers is warranted.

A copy of the poster presentation will be available here.

Defactinib

Title: Phase I study of defactinib combined with pembrolizumab and gemcitabine in patients with advanced cancer
Lead author: Dr. Andrea Wang-Gillam, Washington University in St. Louis
Abstract #: 2561
Summary: FAK is consistently hyperactivated in multiple tumor types including pancreatic ductal adenocarcinoma (PDAC). Previously reported preclinical research showed that FAK and PD-1 inhibitors elicit significant tumor regression, and a maximal response is achieved by combining FAK and PD-1 inhibitors with gemcitabine, suggesting the need for a cytotoxic agent to bolster antigen presentation. In this ongoing Phase 1, dose-escalation study, defactinib is being evaluated in combination with Merck’s PD-1 inhibitor pembrolizumab and gemcitabine in patients with PDAC.

The dose escalation cohort has been completed with a total of 20 patients with refractory solid tumors. Of the 15 patients evaluable for treatment response, 1 (7%) achieved a confirmed PR and 8 (53%) achieved stable disease (SD). Of the 8 PDAC patients, 1 (13%) achieved a confirmed PR and 3 (38%) achieved SD. The median time on treatment was 132 days for all evaluable patients and 158 days for patients with PDAC. Paired biopsies from PDAC patients showed increased proliferating CD8+ T cells and decreased T regs in patients with controlled disease compared to patients with progressive disease. The combination regimen was well tolerated with no dose limiting toxicities, and therefore the RP2D dose was established as defactinib (400mg BID, Days 1-21), pembrolizumab (200mg, Day 1) and gemcitabine (1,000mg/m2, Day 1 and 8). The common treatment-emergent adverse events were anorexia (50%), fatigue (40%), diarrhea (40%), fever (40%) and vomiting (35%), but nearly all were Grade 1/2. There was 1 case of Grade ≥3 diarrhea. An expansion cohort in patients with PDAC is currently ongoing.

A copy of the poster presentation will be available here.

About Duvelisib

Duvelisib is a first-in-class investigational oral, 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 was 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/small lymphocytic lymphoma (CLL/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. Verastem Oncology’s 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) was accepted for filing by the U.S. Food and Drug Administration (FDA), granted Priority Review and assigned a target action date of October 5, 2018. Duvelisib is also being developed by Verastem Oncology 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 Defactinib

Defactinib is an investigational inhibitor of focal adhesion kinase (FAK), a non-receptor tyrosine kinase that mediates oncogenic signaling in response to cellular adhesion and growth factors.7 Based on the multi-faceted roles of FAK, defactinib is used to treat cancer through modulation of the tumor microenvironment and enhancement of anti-tumor immunity.8,9 Defactinib is currently being evaluated in three separate clinical collaborations in combination with immunotherapeutic agents for the treatment of several different cancer types including pancreatic cancer, ovarian cancer, non-small cell lung cancer (NSCLC), and mesothelioma. These studies are combination clinical trials with pembrolizumab and avelumab from Merck & Co. and Pfizer/Merck KGaA, respectively.10,11,12 Information about these and additional clinical trials evaluating the safety and efficacy of defactinib can be found on www.clinicaltrials.gov.