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New Immune Data from Ongoing ADXS-NEO Phase 1 Study Support Clinical Potential for Neoantigen-Directed Immunotherapies

On July 15, 2019 Advaxis, Inc. (NASDAQ: ADXS), a clinical-stage biotechnology company focused on the discovery, development and commercialization of immunotherapy products, reported new immune data from its ongoing ADXS-NEO Phase 1 clinical trial that further support the clinical potential for the company’s platform in neoantigen-directed immunotherapies (Press release, Advaxis, JUL 15, 2019, View Source [SID1234537523]).

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ADXS-NEO is a personalized immunotherapy that is designed to help a patient’s immune system recognize and respond to mutation-derived tumor antigens, or neoantigens, that are unique to his or her tumor. ADXS-NEO is designed to express tLLO fused to up to 40 patient-specific neoantigens arranged sequentially as beads-on-a-string. As a live attenuated bacterial vector, ADXS-NEO can be rapidly taken up by antigen presenting cells, which recognize it as foreign and present the tLLO-NEO fusion proteins to T cells by the major histocompatibility complex class I and II pathways.

ADXS-NEO is being evaluated in an open-label, dose-escalation, multicenter Phase 1 clinical trial in the United States. Part A of the study is open to patients with metastatic non-small cell lung cancer (NSCLC), metastatic microsatellite stable colorectal cancer (MSS-CRC) and metastatic squamous cell carcinoma of the head and neck (SCCHN) who will receive ADXS-NEO as monotherapy. Part B of the study, anticipated to begin later this year, will be open to NSCLC patients as well as patients with melanoma SCCHN and bladder cancer and, for this part, ADXS-NEO will be administered in combination with a checkpoint inhibitor.

The new data were derived from deconvolution of neoantigen pools using single peptides and in vitro stimulation ELISpot assays (minimal CD8+ peptides). This has now been completed for the first two patients enrolled in this study, one with NSCLC and one with MSS-CRC. Highlights of the new post-vaccination data with ADXS-NEO are as follows:

CD8+ T cells were generated against 90% of the 40 neoantigen targets contained in the drug construct for the MSS-CRC patient (the NSCLC patient did not have 40 neoantigen targets and there were certain other issues with this patient’s sample that, together, made it unsuitable for inclusion in this "hit rate" analysis). This is consistent with Advaxis’ previously reported data from its preclinical studies as well as from clinical studies using pooled neoantigen peptides which were presented at the American Association of Cancer Research Annual Meeting last year and earlier this year, respectively. This is the highest "hit rate" publicly reported to-date in the neoantigen field. This high "hit rate", along with the rapid immune responses seen and antigen spreading, lay the foundation for the ADSX-NEO platform to be best-in-class for personalized, neoantigen-directed immunotherapies.

CD8+ T cells were also generated against the hotspot mutations found within each of the two patients’ tumors (i.e., EGFRL858R in the NSCLC patient and KRAS G12A in the MSS-CRC patient). This is important for the ADXS-NEO program as Advaxis believes a number of patient tumors likely will present with hotspot mutations, and generating or maintaining CD8+ T cell activity against these targets may increase the potential for killing cancer cells. All of the first four patients in this Phase 1 trial had a hotspot mutation. This is also relevant for the company’s ADXS-HOT program in that this is the first time Advaxis has observed the ability to generate or maintain specific CD8+ T cell activity against hotspot mutations. Hotspot mutations are important targets contained within the numerous drug constructs within the ADXS-HOT program and the specific hotspot mutations in these two patients, EGFRL858R and KRAS G12A, are included in the company’s ADXS-503 (HOT Lung) and ADXS-508 (HOT Colorectal) drug constructs, respectively.

Antigen spreading was confirmed in the MSS-CRC patient showing specific CD8+ T cells against neoepitopes that were not contained in the drug construct prepared for this patient (the NSCLC patient’s sample was not re-tested for antigen spreading). Thus, Advaxis believes ADXS-NEO may be able to induce a specific immune response against neoantigen-bearing tumor cells with the resultant cell death releasing secondary (nontargeted) tumor antigens. These secondary antigens can then prime subsequent immune responses (antigen spread) that are thought to be responsible for the improved clinical outcomes documented with other immunotherapies. Of note, antigen spreading has also been induced with other Lm constructs such as ADXS-HPV and ADXS-PSA in cervical and prostate cancer patients, respectively.

To date, dosing of ADXS-NEO at 1×108 colony forming units (CFU) has been well-tolerated in two patients. ADXS-NEO dosed at 1×109 CFU was beyond the maximum tolerated dose with reversible Grade 3 hypoxia (n=2) and Grade 3 hypotension (n=1) dose-limiting toxicities.

"This preliminary dataset of the deconvolution assays shows the generation of specific CD8+ T cell response in one MSS-CRC patient against 90% of the neoantigens in that patient’s personalized Lm construct together with antigen spreading, both of which we believe are critical for potential clinical benefit. These encouraging results are consistent with data from our previous preclinical and ELISpot-pooled clinical studies, and we look forward to presenting data from all patients in the monotherapy arm later in the year," said Andres Gutierrez, M.D., Ph.D., Chief Medical Officer of Advaxis. "In addition, we are gaining valuable insight from our ADXS-NEO platform to help advance our ADSX-HOT drug constructs, as for the first time we observed the ability to generate specific CD8+ T cell activity against hotspot mutations in the clinic. We continue to enroll patients in this Phase 1 study for ADXS-NEO and look forward to starting Part B with ADXS-NEO in combination with a checkpoint inhibitor later this year."

AbbVie Enhances Early Stage Oncology Pipeline with Acquisition of Mavupharma

On July 15, 2019 AbbVie (NYSE: ABBV) reported that it has acquired Seattle-based Mavupharma, a privately held biopharmaceutical company focused on novel approaches to target the STING (STimulator of INterferon Genes) pathway for the treatment of cancer (Press release, AbbVie, JUL 15, 2019, View Source [SID1234537522]).

STING pathway signaling plays an important role in the generation of an immune response directed at tumors, and enhancing STING signaling has shown promise in a variety of tumor models. STING pathway stimulation has the potential to increase the susceptibility of tumors and broaden treatment options for patients.

"AbbVie’s vision in oncology is to advance breakthrough areas of science leading to a strong pipeline of innovative cancer therapies," said Steve Davidsen, Ph.D., vice president of oncology discovery, AbbVie. "Mavupharma’s platform has the potential to further our immuno-oncology portfolio and assist in the development of transformative medicines for patients."

Mavupharma’s lead clinical candidate is MAVU-104, a first-in-class, orally active, small molecule inhibitor of ENPP1, an enzyme involved in the regulation of the STING pathway. Inhibiting ENPP1 activity with MAVU-104 allows for highly controlled enhancement of STING signaling in tumors without the need for injections.

"AbbVie has built a leadership position in oncology and their world-class capabilities will enable the accelerated development of our pipeline of STING modulators," said Michael Gallatin, Ph.D., former president and a co-founder of Mavupharma.

"We made tremendous strides in developing our novel STING modulators and advancing MAVU-104 towards the clinic. We are confident in AbbVie’s ability to continue to advance this exciting science for patients," added former chief scientific officer and co-founder Gregory Dietsch, Ph.D.

Financial terms of the transaction were not disclosed.

Vaccitech Appoints Chief Medical Officer to Oversee Development of Growing Clinical Pipeline of T Cell-Inducing Viral Vector Vaccines

On July 15, 2019 Vaccitech, a clinical-stage T cell immunotherapy company developing viral vectors as vaccines to treat and prevent Cancer and Infectious Diseases, reported that it has appointed Mariem Charafeddine as Chief Medical Officer (Press release, Vaccitech, JUL 15, 2019, View Source [SID1234537519]).

Mariem brings over 15 years’ experience in the Biopharmaceutical Industry, spent both advancing the clinical development and commercialisation of Infectious Disease products, and in delivering post-marketing monitoring of licensed medical products. Mariem has previously worked in international medical leadership roles and drug development in Infectious Diseases.

She joins Vaccitech after 6 years at Abbvie, where she most recently served as Medical Director for Pharmacovigilance and Patient Safety Sciences, Infectious Diseases and Neurosciences. Mariem’s prior roles include Global Clinical Development at AbbVie and Hoffmann-La Roche/Genentech, as well as Medical Manager at Hoffmann-La-Roche in France. She is a qualified physician, with clinical practice and research experience focused in Infectious Diseases and Hepatology. Mariem also holds a Master’s degree in Marketing Management, gained from ESCP Europe.

Mariem will oversee the development of Vaccitech’s growing clinical-stage pipeline and will help implement the global clinical development strategy and medical plans across Vaccitech’s therapeutic and prophylactic vaccine products.

"We are delighted to have Mariem join our team as we advance towards the Phase 2b read-outs of our lead clinical program in influenza," said Tom Evans, Vaccitech CEO. "Her wide-ranging clinical development and post-marketing expertise in infectious diseases also puts us in great stead ahead of first in human studies for our HPV and HBV therapeutics. We look forward to her input on how best to develop our vaccines for the patients that need them."

GSK announces positive headline results in Phase 3 PRIMA study of ZEJULA (niraparib) for patients with ovarian cancer in the first line maintenance setting

On July 15, 2019 GlaxoSmithKline plc (LSE/NYSE: GSK) reported positive results from PRIMA (ENGOT-OV26/GOG-3012), the Phase 3 randomized, double-blind, placebo-controlled, study of ZEJULA (niraparib) as a maintenance therapy in patients with first-line ovarian cancer following platinum-based chemotherapy (Press release, GlaxoSmithKline, JUL 15, 2019, View Source [SID1234537517]). The study met its primary endpoint of a statistically significant improvement in progression free survival for women regardless of their biomarker status.

The safety and tolerability profile of niraparib was consistent with previous clinical trials.

Dr Hal Barron, Chief Scientific Officer and President, R&D, GSK, said: "Almost 300,000 women around the world are diagnosed with ovarian cancer every year, yet only about 15% of patients are currently eligible to receive PARP inhibitors as their initial therapy. These exciting data demonstrate that ZEJULA has the potential to significantly benefit even more women with this devastating cancer."

The full results from PRIMA will be presented at an upcoming scientific meeting.

Niraparib is marketed in the United States and Europe under the trade name ZEJULA.

About PRIMA

PRIMA is a double-blind, randomized Phase 3 study designed to evaluate niraparib versus placebo in first-line Stage III or IV ovarian cancer patients. The study assesses the efficacy of niraparib as maintenance treatment, as measured by progression free survival. Platinum responsive patients were randomized 2:1 to niraparib or placebo. The trial incorporated an individualized niraparib starting dose of 200 mg once-daily in patients with baseline weight <77kg or platelet count <150K/μL and 300 mg in all other patients.

About Ovarian Cancer

Approximately 22,000 women are diagnosed each year with ovarian cancer in the United States, and more than 65,000 women are diagnosed annually in Europe. Ovarian cancer is the fifth most frequent cause of cancer death among women. Despite high response rates to platinum-based chemotherapy in the second-line advanced treatment setting, approximately 85% of patients will experience recurrence within two years.

About niraparib

Niraparib is an oral, once-daily PARP inhibitor that is currently being evaluated in three pivotal trials. The ongoing development program for niraparib includes the Phase 3 PRIMA trial, a Phase 3 trial for the treatment of patients with germline BRCA-mutated, metastatic breast cancer (the BRAVO trial), and a registrational Phase 2 treatment trial in patients with ovarian cancer (the QUADRA trial). Several combination studies are also underway, including trials of niraparib plus pembrolizumab in metastatic, triple-negative breast cancer and advanced, platinum-resistant ovarian cancer (the TOPACIO trial) and niraparib plus bevacizumab in recurrent, platinum-sensitive ovarian cancer (the ENGOT-OV24/AVANOVA trial). Janssen Biotech has licensed rights to develop and commercialize niraparib specifically for patients with prostate cancer worldwide, except in Japan.

Important Safety Information for ZEJULA

Myelodysplastic Syndrome/Acute Myeloid Leukaemia (MDS/AML), including some fatal cases, was reported in 1.4% of patients receiving ZEJULA vs 1.1% of patients receiving placebo in Trial 1 (NOVA), and 0.9% of patients treated with ZEJULA in all clinical studies. The duration of ZEJULA treatment in patients prior to developing MDS/AML varied from <1 month to 2 years. All patients had received prior chemotherapy with platinum and some had also received other DNA damaging agents and radiotherapy. Discontinue ZEJULA if MDS/AML is confirmed.

Hematologic adverse reactions (thrombocytopenia, anaemia and neutropenia) have been reported in patients receiving ZEJULA. Grade ≥3 thrombocytopenia, anaemia and neutropenia were reported in 29%, 25%, and 20% of patients receiving ZEJULA, respectively. Discontinuation due to thrombocytopenia, anaemia, and neutropenia occurred, in 3%, 1%, and 2% of patients, respectively. Do not start ZEJULA until patients have recovered from haematological toxicity caused by prior chemotherapy (≤ Grade 1). Monitor complete blood counts weekly for the first month, monthly for the next 11 months of treatment, and periodically thereafter. If haematological toxicities do not resolve within 28 days following interruption, discontinue ZEJULA, and refer the patient to a haematologist for further investigations.

Hypertension and hypertensive crisis have been reported in patients receiving ZEJULA. Grade 3-4 hypertension occurred in 9% of patients receiving ZEJULA vs 2% of patients receiving placebo in Trial 1, with discontinuation occurring in <1% of patients. Monitor blood pressure and heart rate monthly for the first year and periodically thereafter during treatment with ZEJULA. Closely monitor patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension. Manage hypertension with antihypertensive medications and adjustment of the ZEJULA dose, if necessary.

Based on its mechanism of action, ZEJULA can cause foetal harm. Advise females of reproductive potential of the potential risk to a foetus and to use effective contraception during treatment and for 6 months after receiving their final dose. Because of the potential for serious adverse reactions from ZEJULA in breastfed infants, advise lactating women to not breastfeed during treatment with ZEJULA and for 1 month after receiving the final dose.

In clinical studies, the most common adverse reactions (Grades 1-4) in ≥10% of patients included: thrombocytopenia (61%), anaemia (50%), neutropenia (30%), leukopenia (17%), palpitations (10%), nausea (74%), constipation (40%), vomiting (34%), abdominal pain/distention (33%), mucositis/stomatitis (20%), diarrhoea (20%), dyspepsia (18%), dry mouth (10%), fatigue/asthenia (57%), decreased appetite (25%), urinary tract infection (13%), aspartate aminotransferase (AST)/alanine aminotransferase (ALT) elevation (10%), myalgia (19%), back pain (18%), arthralgia (13%), headache (26%), dizziness (18%), dysgeusia (10%), insomnia (27%), anxiety (11%), nasopharyngitis (23%), dyspnoea (20%), cough (16%), rash (21%) and hypertension (20%).

Common lab abnormalities (Grades 1-4) in ≥25% of patients included: decrease in haemoglobin (85%), decrease in platelet count (72%), decrease in white blood cell count (66%), decrease in absolute neutrophil count (53%), increase in AST (36%) and increase in ALT (28%).

Ascentage Pharma announces first patient dosed in Phase I clinical trial of APG-2575 in China as the first China-made Bcl-2 Inhibitor

On July 14, 2019 Ascentage Pharma, a globally-focused, clinical-stage biotechnology company engaged in developing novel therapies for cancers, hepatitis B virus and age-related diseases, reported that the company recently dosed the first patient successfully in a Phase I clinical trial of APG-2575, a novel Bcl-2 selective inhibitor, for the treatment of hematologic malignancies in China (Press release, , JUL 14, 2019, View Source [SID1234537515]). The Company also has an ongoing multi-center Phase I dose-escalation study of APG-2575 as a single agent in the United States and Australia. APG-2575 could potentially be the first China-made Bcl-2 inhibitor.

APG-2575 is a novel, orally administered Bcl-2 selective inhibitor. It is designed to treat hematologic malignancies by selective blocking Bcl-2 to restore the normal apoptosis process in cancer cells.

Bcl-2 is the founding member of the Bcl-2 family proteins which are most notable for their critical roles in the regulation of apoptosis through the formation of heterodimers with pro-apoptotic proteins (BIM, BAD and most others). Due to the very large and hydrophobic interfaces of Bcl-2 proteins, it is difficult to develop a drug that targets Bcl-2 family protein. The marketed Bcl-2 inhibitor venetoclax/ABT-199 approved by the U.S. FDA in April 2016 has validated the clinical basis for further targeted drug development. Ascentage Pharma’s APG-2575 is one of the few Bcl-2 selective inhibitors in active clinical trials other than Venetoclax.

This Phase I trial is designed to assess the safety and tolerance of APG-2575 in patients with hematologic malignancies and confirm the maximal tolerated dose (MTD) or recommended Phase II dose (RP2D) of APG-2575. Included in this trial are patients with acute myelogenous leukemia (AML), non-Hodgkin’s lymphoma (NHL). Currently, the first patient enrolled in China has been dosed at Institute of Hematology, Blood Disease Hospital of Chinese Academy of Medical Sciences during the first stage of dose-escalation.

The Phase I dose-escalation clinical trial of APG-2575 in the United States and Australia is being conducted at several academic institutions including MD Anderson Cancer Center and Mayo Clinic. Included in this trial are patients with various types of blood cancer, such as CLL, NHL, MM, AML. At present, 4 dose cohorts have been completed in the United States and Australia. Preliminary data suggested that APG-2575 was well tolerated and safe, it had promising anti-tumor activity in the treatment of relapsed/refractory CLL.

During the 2019 American Association for Cancer Research (AACR) (Free AACR Whitepaper) annual meeting, Ascentage Pharma released several preclinical research results of APG-2575, which demonstrated the potential in combination therapy.

"APG-2575 is a key product in our development pipeline of apoptosis. Initiating the clinical trial in China represents a new step in our global clinical development. We believe that APG-2575 may provide more therapy options to patients with blood diseases," said Dr. Dajun Yang, Chairman and CEO of Ascentage Pharma.

About APG-2575
APG-2575 is a novel, orally administered Bcl-2 selective inhibitor developed by Ascentage Pharma. It is designed to treat hematologic malignancies by selective blocking Bcl-2 to restore the normal apoptosis process in cancer cells.

The Company recently initiated a phase I clinical trial of APG-2575 in China, which is the first domestic Bcl-2 selective inhibitor entered the clinical stage. Ascentage previously has initiated a multi-center Phase I dose-escalation study of APG-2575 as a single agent in multiple hematologic malignancies in the United States and Australia in August 2018.