On May 15, 2020 Clovis Oncology, Inc. (NASDAQ: CLVS), reported that the U.S. Food and Drug Administration (FDA) approved Rubraca (rucaparib) tablets for the treatment of adult patients with a deleterious BRCA mutation (germline and/or somatic)-associated metastatic castration-resistant prostate cancer (mCRPC) who have been treated with androgen receptor-directed therapy and a taxane-based chemotherapy (Press release, Clovis Oncology, MAY 15, 2020, View Source [SID1234558152]). The FDA approved this indication under accelerated approval based on objective response rate (ORR) and duration of response (DOR) data from the multi-center, single arm TRITON2 clinical trial. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. The TRITON3 clinical trial is expected to serve as the confirmatory study for the Rubraca accelerated approval in mCRPC. Warning and precautions include myelodysplastic syndrome (MDS), acute myeloid leukemia (AML) and embryo-fetal toxicity. Please see additional warnings and precautions and select safety information below.i

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"Standard treatment options for men with mCRPC have been limited to androgen receptor-targeting therapies, taxane chemotherapy, Radium-223 and sipuleucel-T," said Wassim Abida, M.D., Medical Oncologist, Memorial Sloan Kettering Cancer Center, and Principal Investigator for the TRITON2 study. "Rubraca is the first in a class of drugs to become newly available to patients with mCRPC who harbor a deleterious BRCA mutation. Given the level and duration of responses observed with Rubraca in men with mCRPC and these mutations, it represents an important and timely new treatment option for this patient population."

The FDA approval for this third indication for Rubraca is based on efficacy data from patients with mCRPC and a deleterious BRCA mutation (germline and/or somatic) enrolled in the multi-center, single arm TRITON2 (NCT02952534) clinical trial. The major efficacy outcomes are confirmed ORR and DOR by modified RECIST version 1.1/PCWG3 criteria assessed by blinded independent radiologic review (IRR). Confirmed prostate-specific antigen (PSA) response rate is an additional prespecified endpoint.i,ii

Evaluable patient populations in the supplemental New Drug Application dataset included the following: 62 RECIST-evaluable patients with a BRCA (germline and/or somatic) mutation and measurable disease (IRR); 115 patients with a BRCA (germline and/or somatic) mutation and measurable or non-measurable disease; and 209 patients with HRD-positive mCRPC enrolled in TRITON2. Patients should be selected for treatment of mCRPC with Rubraca based on the presence of a deleterious BRCAmutation (germline and/or somatic).i

Efficacy outcomes and safety results are summarized belowi:

44% ORR (N=62; 95% CI 31, 57) by blinded-IRR assessment.
Objective response rates were similar for patients with a germline
BRCA
versus somatic
BRCA
mutation.
Median DOR by blinded-IRR assessment was not evaluable (NE) at data cut-off.

Rubraca

(N=62)

Confirmed Objective Response Rate (95% CI)a

44% (31, 57)

Median DOR in months (95% CI)b

NE (6.4, NE)

NE = not evaluable

aDefined per modified RECIST v1.1 criteria and with no confirmed bone progression per PCWG3.

bThe range for the DOR was 1.7-24+ months. Fifteen of the 27 (56%) patients with a confirmed objective response had a DOR of ≥ 6 months.

Additionally, a 55% confirmed prostate specific antigen (PSA) response rate (95% CI 45, 64) was observed in an analysis of 115 patients with a deleterious BRCA mutation (germline and/or somatic) and measurable or non-measurable disease.ii

The safety evaluation of Rubraca 600 mg twice daily as monotherapy treatment is based on an analysis of 209 patients with HRD-positive mCRPC from the multi-center, single arm TRITON2 clinical study, including 115 with BRCA-mutated mCRPC. The most common adverse reactions (greater than or equal to 20% of patients; CTCAE Grade 1-4) occurring in the BRCA mutant population (n=115) were asthenia/fatigue, nausea, anemia, ALT/AST increased, decreased appetite, constipation, rash, thrombocytopenia, vomiting, and diarrhea. The most common laboratory abnormalities (greater than or equal to 35% of patients; CTCAE Grade 1-4) were increase in ALT, decrease in leukocytes, decrease in phosphate, decrease in absolute neutrophil count, decrease in hemoglobin, increase in alkaline phosphatase, increase in creatinine, increase in triglycerides, decrease in lymphocytes, decrease in platelets, and decrease in sodium.i

"The data from the TRITON2 clinical trial supporting the FDA approval of Rubraca in mCRPC have been highly consistent over time, and we are pleased that the FDA has granted an accelerated approval for Rubraca in this third indication," said Patrick J. Mahaffy, President and CEO of Clovis Oncology. "We are proud to offer Rubraca as a new treatment option to physicians and eligible prostate cancer patients with a deleterious BRCA mutation beginning today."

"The FDA approval of Rubraca is a significant milestone for patients with metastatic castration-resistant prostate cancer and a deleterious BRCA mutation," said Howard Soule, Ph.D., Executive Vice President and Chief Science Officer of the Prostate Cancer Foundation. "Although new treatments for prostate cancer have been approved in recent years, most men living with advanced stages of this disease continue to face a difficult journey with few treatment options."

About Prostate Cancer

The American Cancer Society estimates that nearly 192,000 men in the United States will be diagnosed with prostate cancer in 2020iii, and the GLOBOCAN Cancer Fact Sheets estimated that approximately 450,000 men in Europe were diagnosed with prostate cancer in 2018.iv Castration-resistant prostate cancer has a high likelihood of developing metastases. Metastatic castration-resistant prostate cancer, or mCRPC, is an incurable disease, usually associated with poor prognosis. Approximately 43,000 men in the U.S. are expected to be diagnosed with mCRPC in 2020.v According to the American Cancer Society, the five-year survival rate for mCRPC is approximately 30 percent.vi Approximately 12 percent of patients with mCRPC harbor a deleterious germline and/or somatic mutation in the genes BRCA1 and BRCA2. These molecular markers may be used to select patients for treatment with a PARP inhibitor.vii

Rubraca U.S. FDA Approved Indication

Rubraca is indicated for the treatment of adult patients with a deleterious BRCA mutation (germline and/or somatic)-associated metastatic castration-resistant prostate cancer (mCRPC) who have been treated with androgen receptor-directed therapy and a taxane-based chemotherapy.

This indication is approved under accelerated approval based on objective response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

Select Important Safety Information

Myelodysplastic Syndrome (MDS)/Acute Myeloid Leukemia (AML) has occurred in patients treated with Rubraca, and are potentially fatal adverse reactions. In 1146 treated patients, MDS/AML occurred in 20 patients (1.7%), including those in long term follow-up. Of these, 8 occurred during treatment or during the 28 day safety follow-up (0.7%). The duration of Rubraca treatment prior to the diagnosis of MDS/AML ranged from 1 month to approximately 53 months. The cases were typical of secondary MDS/cancer therapy-related AML; in all cases, patients had received previous platinum-containing regimens and/or other DNA damaging agents. In TRITON2, MDS/AML was not observed in patients with mCRPC (n=209) regardless of homologous recombination deficiency (HRD) mutation.

Do not start Rubraca until patients have recovered from hematological toxicity caused by previous chemotherapy (≤ Grade 1). Monitor complete blood counts for cytopenia at baseline and monthly thereafter for clinically significant changes during treatment. For prolonged hematological toxicities (> 4 weeks), interrupt Rubraca or reduce dose and monitor blood counts weekly until recovery. If the levels have not recovered to Grade 1 or less after 4 weeks or if MDS/AML is suspected, refer the patient to a hematologist for further investigations, including bone marrow analysis and blood sample for cytogenetics. If MDS/AML is confirmed, discontinue Rubraca.

Based on findings in genetic toxicity and animal reproduction studies, advise male patients with female partners of reproductive potential or who are pregnant to use effective methods of contraception during treatment and for 3 months following last dose of Rubraca. Advise male patients not to donate sperm during therapy and for 3 months following the last dose of Rubraca.

Most common adverse reactions in TRITON2 (≥ 20%; Grade 1-4) were fatigue/asthenia (62%), nausea (52%), anemia (43%), AST/ALT elevation (33%), decreased appetite (28%), rash (27%), constipation (27%), thrombocytopenia (25%), vomiting (22%), and diarrhea (20%).

Co-administration of rucaparib can increase the systemic exposure of CYP1A2, CYP3A, CYP2C9, or CYP2C19 substrates, which may increase the risk of toxicities of these drugs. Adjust dosage of CYP1A2, CYP3A, CYP2C9, or CYP2C19 substrates, if clinically indicated. If co-administration with warfarin (a CYP2C9 substrate) cannot be avoided, consider increasing frequency of international normalized ratio (INR) monitoring.

Click here for full Prescribing Information for Rubraca.

You may also report side effects to Clovis Oncology, Inc. at 1-415-409-7220 (US toll) or 1-844-CLVS-ONC (1-844-258-7662; US toll-free).

About Accessing Rubraca

Rubraca is available in the United States through specialty pharmacies and distributors. Clovis is committed to ensuring Rubraca access for patients and offers eligible patients financial and reimbursement support through Rubraca Connections. More information about Rubraca Connections is available at RubracaConnections.com or by calling 1-844-779-7707 between 8 a.m. and 8 p.m. Eastern Time, Monday through Friday.

About Rubraca (rucaparib)

Rucaparib is an oral, small molecule inhibitor of PARP1, PARP2 and PARP3 being developed in multiple tumor types, including ovarian and metastatic castration-resistant prostate cancers, as monotherapy, and in combination with other anti-cancer agents. Exploratory studies in other tumor types are also underway.

On May 15, 2020 VBI Vaccines Inc. (Nasdaq: VBIV) (VBI), a commercial-stage biopharmaceutical company developing next-generation infectious disease and immuno-oncology vaccines, reported that expanded immunologic and tumor response data from the ongoing Phase 1/2a study of VBI-1901, the Company’s cancer vaccine immunotherapeutic candidate, in recurrent glioblastoma (GBM) patients will be presented at the 2020 American Association for Cancer Research (AACR) (Free AACR Whitepaper) Virtual Annual Meeting II, to be held June 22-24, 2020 (Press release, VBI Vaccines, MAY 15, 2020, View Source [SID1234558151]).

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In his presentation of the e-poster via an accompanying audio narrative, David E. Anderson, Ph.D., VBI’s Chief Scientific Officer, will describe how the highest dose of VBI-1901 in combination with granulocyte-macrophage colony-stimulating factor (GM-CSF) boosted cytomegalovirus (CMV) immunity, even in highly immunosuppressed patients. Moreover, a baseline biomarker was identified in patients in the Part A dose-ranging phase of the study that may help predict patients most likely to respond to, and derive clinical benefit from, treatment with VBI-1901. The correlation observed between baseline biomarker data and tumor response data in Part A of the trial was strengthened by the inclusion of additional patients in the Part B extension phase of the study.

Additional information, including a detailed description of the study design, eligibility criteria, and investigator sites, is available at ClinicalTrials.gov using identifier NCT03382977.

Poster Presentation/Session Details

-Title: CMV-specific immuno-dysregulation in recurrent glioblastoma patients can be overcome with therapeutic vaccination which is associated with tumor response and overall survival benefits in a Phase I/IIA study
-Abstract: 6538
-Session: Therapeutic Antibodies 5 / Vaccines
-Date: June 22 – 24, 2020
-Event Website: View Source

About the Phase 1/2a Study Design

VBI’s two-part Phase 1/2a study is a multi-center, open-label, dose-escalation study of VBI-1901 in up to 38 patients with recurrent GBM:

●Phase 1 (Part A)

●Dose-escalation phase that defined the safety, tolerability, and optimal dose level of VBI-1901 adjuvanted with granulocyte-macrophage colony-stimulating factor (GM-CSF) in recurrent GBM patients with any number of prior recurrences.
●This phase enrolled 18 recurrent GBM patients across three dose cohorts of VBI-1901: 0.4 µg, 2.0 µg, and 10.0 µg.
●Enrollment completed in December 2018.

●Phase 2a (Part B)

●Subsequent extension of the optimal dose level, 10.0 µg, as defined in the Part A dose escalation phase.
●This phase is a two-arm study, enrolling 10 first-recurrent GBM patients in each arm, assessing 10.0 µg of VBI-1901 in combination with either GM-CSF or GSK’s proprietary AS01B adjuvant system as immunomodulatory adjuvants.
Enrollment of the 10 patients in the GM-CSF arm is complete. Enrollment of the 10 patients in the AS01B arm is ongoing.

VBI-1901 is administered intradermally when adjuvanted with GM-CSF and intramuscularly when adjuvanted with the AS01B adjuvant system. Patients in both phases of the study receive the vaccine immunotherapeutic every four weeks until tumor progression.

About VBI-1901 and GBM

VBI-1901 is a novel cancer vaccine immunotherapeutic candidate developed using VBI’s enveloped virus-like particle (eVLP) technology to target two highly immunogenic cytomegalovirus (CMV) antigens, gB and pp65. Scientific literature suggests CMV infection is prevalent in multiple solid tumors, including glioblastoma (GBM). GBM is among the most common and aggressive malignant primary brain tumors in humans. In the U.S. alone, 12,000 new cases are diagnosed each year. The current standard of care for treating GBM is surgical resection, followed by radiation and chemotherapy. Even with aggressive treatment, GBM progresses rapidly and is exceptionally lethal.

On May 15, 2020 GlycoMimetics, Inc. (Nasdaq: GLYC) reported that preclinical research on two of its drug candidates, uproleselan and GMI-1359, will be shared at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2020, which will now be held virtually from June 22-24 (Press release, GlycoMimetics, MAY 15, 2020, View Source [SID1234558150]).

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During the June session, GlycoMimetics will present preclinical data that further support the potential of the Company’s compounds to be used in the treatment of acute myeloid leukemia (AML) as well as in the setting of stem cell transplantation. Additionally, new information will be presented on the ability of transcriptome profiling to identify those tumor types most likely to benefit from targeted E-selectin inhibition, a key mechanism of GlycoMimetics drug candidates, supporting their potential uses in a biomarker-driven approach.

Important findings from the preclinical research include:

– Co-targeting and inhibition of E-selectin/CXCR4/FLT3 with GMI-1359 in combination with sorafenib exerts protection of normal hematopoiesis (blood cell formation) and more efficiently reduces leukemic burden compared to sorafenib alone, resulting in extended overall survival, in a patient-derived FLT3 resistant AML model;

– Inhibition of E-selectin with uproleselan during pre-transplant conditioning results in increased survival of mice in a hematopoietic stem cell transplantation and reconstitution model; and,

– Further analysis of E-selectin glycosylation genes extends the prognostic importance of this unique gene signature in AML, highlighting the potential use of uproleselan in AML and other hematologic malignancies.

"We look forward to presenting data at this year’s AACR (Free AACR Whitepaper) meeting that will support our approach to targeting E-selectin with both uproleselan and GMI-1359 as part of potential treatment regimens for patients with AML and other diseases," said John Magnani, Ph.D., GlycoMimetics Senior Vice President and Chief Scientific Officer. "Furthermore, the new data around glycosylation gene signatures highlights a potential biomarker-driven approach in targeting E-selectin."

Of note, data will be presented demonstrating that lethality of the FLT-3 mutation is specifically dependent upon high levels of E-selectin ligand expressed on the surface of AML blasts. FLT-3 ITD AML patients are known to express higher levels of E-selectin on the vasculature endothelium. In the patient data to be reported at the AACR (Free AACR Whitepaper) meeting, patients who had the FLT-3 ITD mutation, but presented low levels of E-selectin ligand on their AML cells, did not experience worse outcomes, whereas those who did have FLT-3 ITD with high levels of E-selectin ligand, experienced poor survival. This adds support to the key role of E-selectin ligand in contributing to poor outcomes in AML and to the potential of uproleselan to improve AML treatment.

Details on GlycoMimetics’ presentations at the upcoming virtual AACR (Free AACR Whitepaper) meeting include:

Abstract Control #7924/ Permanent Abstract #5867:
"Transcriptome profiling of ST3GAL4 and FUT7 in multiple tumor types and prognostic value in adult acute myeloid leukemia"

Session Type: Poster Session

Session Category: Molecular and Cellular Biology / Genetics

Session Title: Functional Genomics and Other Topics

Abstract Control #3865/ Permanent Abstract #486:
"Enhanced survival of lethally-irradiated mice with HSC reconstitution in combination with the E-selectin antagonist, GMI-1271 (uproleselan)"

Session Type: Poster Session

Session Category: Tumor Biology

Session Title: Stem Cells, Cancer Stem Cell Therapeutic Targeting, and Regenerative Medicine

Abstract #5038:
"Combined Targeting of E-selectin/CXCR4 and FLT3 by GMI-1359 and Sorafenib Effectively Reduces Leukemia Cell Burden and Protects Normal Hematopoiesis in a Patient-derived AML Xenograft Model"

Session Type: Poster Session

Session Category: Tumor Biology

Session Title: Drug Targets in the Microenvironment

Meeting abstracts are available at AACR (Free AACR Whitepaper)’s website.

About Uproleselan

Discovered and developed by GlycoMimetics, uproleselan and GMI-1687 are investigational, first-in-class, targeted inhibitors of E-selectin. Uproleselan (yoo’ pro le’ sel an), currently in a comprehensive Phase 3 development program in AML, has received Breakthrough Therapy Designation from the U.S. FDA for the treatment of adult AML patients with relapsed or refractory disease. Uproleselan is designed to block E-selectin (an adhesion molecule on cells in the bone marrow) from binding with blood cancer cells as a targeted approach to disrupting well-established mechanisms of leukemic cell resistance within the bone marrow microenvironment. In a Phase 1/2 clinical trial, uproleselan was evaluated in both newly diagnosed elderly and relapsed or refractory patients with AML. In both populations, patients treated with uproleselan together with standard chemotherapy achieved better-than-expected remission rates and overall survival compared to historical controls, which have been derived from results from third-party clinical trials evaluating standard chemotherapy, as well as lower-than-expected induction-related mortality rates. Treatment in these patient populations was generally well-tolerated, with fewer than expected adverse effects.

About GMI-1359

GMI-1359 is designed to simultaneously inhibit both E-selectin and CXCR4. E-selectin and CXCR4 are both adhesion molecules involved in tumor trafficking and metastatic spread. Preclinical studies indicate that targeting both E-selectin and CXCR4 with a single compound could improve efficacy in the treatment of cancers that involve the bone marrow such as AML and multiple myeloma or in solid tumors that metastasize to the bone, such as prostate cancer and breast cancer, as well as in osteosarcoma, a rare pediatric tumor. GMI-1359 has completed a Phase 1 clinical trial in healthy volunteers. The Duke University Phase 1b clinical study in breast cancer patients is designed to enable investigators to identify an effective dose of the drug candidate and to generate initial biomarker data around the drug’s activity. GMI-1359 has received Orphan Drug Designation and Rare Pediatric Disease Designation from the FDA for the treatment of osteosarcoma, a rare cancer affecting about 900 adolescents a year in the United States.

On May 15, 2020 Vividion Therapeutics, a biotechnology company discovering and developing highly selective small molecule medicines that drug traditionally inaccessible targets, reported data describing the application of Vividion’s screening platform to discover a highly selective and potent covalent engager of a previously undrugged E3 ligase (Press release, Vividion Therapeutics, MAY 15, 2020, View Source [SID1234558149]). Data will be presented in a poster during the 2020 American Association for Cancer Research (AACR) (Free AACR Whitepaper) Virtual Annual Meeting II, being held from June 22-24, 2020. All poster presentations will be made available online on the first day of the meeting.

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"Our proprietary platform allows us to discover highly selective small molecules against previously undruggable targets, exemplified by the data we are presenting at AACR (Free AACR Whitepaper), which shows unparalleled selectivity and potency for a novel E3 ligase," said Diego Miralles, M.D., Chief Executive Officer of Vividion. "E3 ligases are an important class of proteins responsible for directing target proteins to the proteasome for degradation and have the potential to unlock a wide range of valuable therapeutic applications. To the best of our knowledge, our program represents the first E3 ligase outside of Cereblon and VHL that has been reported in a bifunctional construct to achieve in vivo degradation of multiple targets. In addition to data described in our abstract, we have additional evidence that by leveraging covalent binding, we can achieve differentiated pharmacology with profound and long lasting-protein degradation, which may enable us to offer an improved treatment compared to existing approaches."

When Vividion’s ligands were used to build bispecific degraders, they demonstrated degradation of all targets tested in vitro at concentrations less than 10 nanomolar and achieved near complete degradation of the intended target across multiple tissues in vivo. The constructs were consistently more potent both in vitro and in vivo compared to several published Cereblon- and VHL- based degraders designed to target the same proteins.

Poster Presentation Details:
Abstract # 6411
Title: Discovery of covalent ligands to novel E3 ligases enables bispecific degraders with highly differentiated protein degradation across a broad range of targets
Authors: Kristen Baltgalvis, Shota Kikuchi, Kent Symons, Joe Klebba, Lena Luukkonen, Yuta Naro, Colin Walsh, Joon Chang, Charles Chapman, Ali Tabatabaei, Brian Nordin, Christie Eissler, Joel Chick, Landon Whitby, Jaclyn Brannon, Gabe Simon, Matt Patricelli, Dean Stamos, Larry Burgess, Todd Kinsella
Session Category: Experimental and Molecular Therapeutics
Session Title: Novel Therapeutic Approaches

On May 15, 2020 ImmunSYS, Inc., a clinical- stage biopharmaceutical company focused on the development of innovative cancer immunotherapy products, reported that results from a proof of concept (PoC) study evaluating its proprietary immunotherapy platform, YourVaccx, for the treatment of patients with metastatic solid tumor cancers will be presented at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) 2020 Virtual Annual Meeting II being held June 22 – 24 (Press release, ImmunSYS, MAY 15, 2020, View Source;utm_medium=rss&utm_campaign=immunsys-announces-upcoming-presentation-at-aacr-virtual-annual-meeting-ii [SID1234558146]).

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The poster (#6540) entitled, "Regression of metastatic cancer and abscopal effects following in situ vaccination by cryosurgical tumor cell lysis and intratumoral immunotherapy: A case series" will be presented by Gary Onik, M.D.

ImmunSYS’s abstract can be found at www.aacr.org

Following the presentation, a copy of the poster will be posted on www.immunsys.com