On July 6, 2022 CytomX Therapeutics, Inc. (Nasdaq: CTMX), a leader in the field of conditionally activated oncology therapeutics, reported that the Phase 2 study of praluzatamab ravtansine in patients with hormone receptor-positive (HR+)/human epidermal growth factor receptor 2 (HER2)-non-amplified breast cancer (Arm A) met its primary efficacy endpoint of confirmed objective response rate (ORR) of greater than 10 percent by central radiology review (Press release, CytomX Therapeutics, JUL 6, 2022, View Source [SID1234616502]). Praluzatamab ravtansine is a DM4-conjugated, conditionally activated antibody-drug conjugate (ADC) targeting CD166 and is wholly owned by CytomX.

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As of the data cutoff on May 13, 2022, 47 patients unselected for CD166 expression with advanced HR+/HER2-non-amplified breast cancer were evaluable for the primary efficacy endpoint. The ORR by central radiology review was 15 percent. Clinical benefit rate at 24 weeks by investigator (CBR24), as defined in the protocol as any response (confirmed or unconfirmed) or stable disease for 24 weeks, was 40 percent; median progression-free survival was 2.6 months. All patients in Arm A were treated at the initial Phase 2 starting dose of 7 mg/kg administered every three weeks. Arm B did not pass protocol-defined futility boundary (ORR was less than 10%) in patients with advanced triple-negative breast cancer (TNBC) and enrollment into Arms B and C will be discontinued.

As of this data cut, the safety profile of praluzatamab ravtansine in Arm A was generally consistent with toxicities observed in Phase 1 and with the DM4 payload; namely, high-grade toxicities or toxicities resulting in dose modifications were predominantly ocular or neuropathic in nature. Thirty percent of patients discontinued treatment for an adverse event (AE). Grade 3+ ocular and neuropathic toxicities were 15 and 10 percent, respectively. Arm B evaluated both 7 mg/kg and 6 mg/kg in patients with TNBC. The toxicity profile of 7 mg/kg starting dose was consistent with Arm A. In the 6 mg/kg cohort, no patients discontinued treatment for an AE and Grade 3+ ocular or neuropathic related events were lower at 3, and 0 percent, respectively. Biomarker analysis is ongoing. CytomX intends to submit data from this study for presentation at a medical conference in the second half of 2022.

"These results from our Phase 2 evaluation of praluzatamab ravtansine support single-agent activity of this novel drug candidate in hormone receptor-positive breast cancer where significant unmet need remains," said Sean McCarthy, D.Phil., chief executive officer and chairman at CytomX Therapeutics. "However, we do not believe the median progression-free survival at 7 mg/kg supports further evaluation at this dose. While we are encouraged by the emerging safety profile of 6 mg/kg, we do not plan to further advance this program alone given current financial market conditions and will be seeking a partnership."

Kathy D. Miller, MD, Ballvé Lantero Professor of Oncology, Indiana University Simon Comprehensive Cancer Center, Indianapolis, Indiana, and lead investigator of the Phase 2 study stated, "In this Phase 2 study, praluzatamab ravtansine showed single-agent activity in an unselected population of patients with advanced HR+/HER2-non-amplified breast cancer; additional clinical studies at 6 mg/kg are warranted."

Conference Call & Webcast
CytomX management will host a conference call and a simultaneous webcast today at 5:00 pm ET (2:00 pm PT) to discuss these results. Participants may register for the conference call here and are advised to do so at least 10 minutes prior to joining the call. A live webcast of the call can be accessed via the Events and Presentations page of CytomX’s website at View Source

About Praluzatamab Ravtansine
Praluzatamab ravtansine is a conditionally activated antibody-drug conjugate (ADC) comprised of a CD166-directed humanized monoclonal antibody conjugated to the maytansinoid DM4, a tubulin inhibitor. Praluzatamab ravtansine utilizes CytomX Probody platform technology, which incorporates a masking peptide to cover and block the cellular binding region of the antibody. Tethered to the antibody via a protease-cleavable linker, the masking peptide is designed to be removed in a protease-rich tumor microenvironment, enabling the ADC to be unmasked and engage its target to deliver the toxic DM4 payload inside tumor cells. The goal is to have praluzatamab ravtansine remain inert while in circulation to limit binding in healthy tissues until it is activated by tumor-associated proteases. Praluzatamab ravtansine was evaluated in a three-arm Phase 2 study (NCT04596150) in patients with hormone receptor-positive/HER2-non-amplified breast cancer and patients with triple-negative breast cancer.

About the Phase 2 Study of Praluzatamab Ravtansine in Breast Cancer (NCT04596150)
Arm A of the study evaluated praluzatamab ravtansine as monotherapy (7 mg/kg, Q3W) in patients with inoperable, locally advanced or metastatic hormone receptor-positive/human epidermal growth factor receptor 2 (HER2)-non-amplified breast cancer. Patients received 0 to 2 prior cytotoxic chemotherapies in the inoperable, locally advanced, or metastatic setting, regardless of the level of CD166 expression.

Arm B assessed praluzatamab ravtansine as a single agent (6 or 7 mg/kg, Q3W) in patients with inoperable, locally advanced or metastatic triple-negative breast cancer (TNBC). Patients received 1 to 3 prior lines of chemotherapy for inoperable, locally advanced, or metastatic disease and had CD166 expression.

Arm C studied praluzatamab ravtansine (6 mg/kg, Q3W) in combination with pacmilimab (1200 mg, Q3W), CytomX’s proprietary conditionally activated anti-PD-L1 antibody, in patients with TNBC. Eligibility was the same as Arm B with the additional requirement that patients’ tumors were programmed death-ligand 1 (PD-L1)-positive by an FDA-approved test.

On July 6, 2022 Elicio Therapeutics, a clinical stage biotechnology company developing a pipeline of novel immunotherapies for the treatment of cancer and other diseases, reported that it presented preclinical data demonstrating its Amphiphile (AMP) platform adjuvant AMP-CpG combined with cell surface-associated viral protein EBV gp350 and EBVpoly protein, elicits a robust and durable immune response to Epstein-Barr virus (EBV) (Press release, Elicio Therapeutics, JUL 6, 2022, View Source [SID1234616503]). EBV gp350 is expressed on the outside of the virus and on the cells producing the virus, making it a major target for neutralizing antibodies and CD4+ T cells, while EBVpoly protein contains multiple epitopes for CD8+ T cells. The data was presented at the 2022 Keystone Symposia on Viral Immunity Basic Mechanisms and Therapeutic Applications virtually and in-person at the Keystone Resort in Keystone, CO from June 29-July 2, 2022. The electronic poster is accessible here.

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EBV is a herpesvirus responsible for the well-known mononucleosis infections ("mono") and has also been implicated in multiple lymphoid and epithelial cancers. EBV targets both B cells and epithelial cells and utilizes their molecular machinery to replicate the viral genome. The virus causes B cells to differentiate into memory B cells, which then can move into the circulatory system, or become latent until a trigger causes reactivation. Approximately 95%[1] of the adult population worldwide is infected with EBV which persists for the life of the individual, however, there is currently no approved vaccine.

"Vaccines against EBV have historically been difficult to develop because of the associated viral latency, persistence and immune modulation properties which enable it to evade effective antibody targeting," said Lisa McNeil, Ph.D., Head of Translational Medicine at Elicio Therapeutics. "These data reinforce what we’ve seen in previous studies with our AMP platform, demonstrating the potent and durable immune responses elicited by delivering a therapeutic payload direct to the lymph nodes, the control center of the immune system. By targeting the most abundant glycoprotein expressed on the virus with the AMP-CpG adjuvant, in a mouse model mimicking human-specific immune responses to viral infection, we were able to induce neutralizing antibodies and strong T cell responses. This holds great promise for prevention of EBV associated diseases and controlling the spread of latently infected B cells."

The EBV vaccine is based on the research of Dr. Rajiv Khanna, Professor, Senior Scientist and Coordinator of QIMR Berghofer’s Centre for Immunotherapy and Vaccine Development. Professor Khanna said, "I am encouraged by the data demonstrating the potential of the AMP-CpG adjuvant combined with the EBV proteins to not only activate but supercharge the immune system as shown by the high frequencies of polyfunctional gp350-specific CD4+ T cells and EBVpoly-specific CD8+ T cells induced in this model."

Poster Presentation Details

Title: A Lymph Node Targeted Engineered Subunit Antigen and Molecular Adjuvant Vaccine Promotes Potent Cellular and Humoral Immunity to Epstein Barr Virus in HLA-expressing Mice

Highlights from the Poster

EBVpoly is a polyepitope protein developed at QIMR Berghofer Medical Research Institute that includes 20 CD8+ T cell epitopes from EBV latent and lytic antigens with broad coverage against multiple HLA types.
AMP-CpG delivers adjuvant directly to lymph nodes, boosting the immune response to protein antigens.
Vaccination with AMP-CpG combined with EBV gp350 and EBVpoly proteins rapidly induced potent gp350-specific IgG and EBV neutralizing antibody responses in HLA transgenic mice.
AMP-CpG immunization induced high frequencies of polyfunctional gp350-specific CD4+ T cells and EBVpoly-specific CD8+ T cells.
The potent humoral and cellular immunity induced by AMP-CpG was durable, with responses maintained for >7 months.
The broad coverage against multiple viral determinants and the AMP-CpG adjuvant are likely to provide better protection against primary EBV infection while the strong T cell responses will be critical in controlling the spread of latently infected B cells and the development of EBV-associated diseases, such as malignancies and multiple sclerosis.
About the Amphiphile Platform

Our proprietary Amphiphile, or AMP, platform delivers investigational immunotherapeutics directly to the "brain center" of the immune system – the lymph nodes. We believe this site-specific delivery of disease-specific antigens, adjuvants and other immunomodulators may efficiently educate, activate and amplify critical immune cells, potentially resulting in induction and persistence of potent adaptive immunity required to treat many diseases. In preclinical models, we have observed lymph node-specific engagement driving therapeutic immune responses of increased magnitude, function and durability. We believe our AMP lymph node-targeted approach will produce superior clinical benefits compared to immunotherapies that do not engage the lymph nodes.

Our AMP platform, originally developed at the Massachusetts Institute of Technology, or MIT, has broad potential across cancers, infectious diseases and other disease indications to advance a number of development initiatives through internal activities, in-licensing arrangements or development collaborations and partnerships.

The Amphiphile platform is thought to deliver immunotherapeutics directly to the lymph nodes by latching on to the protein albumin, found in the bloodstream, as it travels to lymphatic tissue. In preclinical models, we have observed lymph node-specific engagement driving therapeutic immune responses of increased magnitude, function and durability.

On July 6, 2022 Global Coalition for Adaptive Research (LARKSPUR, CA), Biohaven Pharmaceutical Holding Company Ltd. (NYSE: BHVN), and Vigeo Therapeutics — The Global Coalition for Adaptive Research (GCAR) in collaboration with Biohaven and Vigeo Therapeutics, reported the activation of Biohaven’s troriluzole and Vigeo’s VT1021 in GBM AGILE (Glioblastoma Adaptive Global Innovative Learning Environment) (Press release, Biohaven Pharmaceutical, JUL 6, 2022, View Source [SID1234616519]). GBM AGILE is a revolutionary patient-centered, adaptive platform trial for registration that tests multiple therapies for patients with newly-diagnosed and recurrent glioblastoma (GBM) – the deadliest form of brain cancer.

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Biohaven’s troriluzole and Vigeo’s VT1021 are entering the GBM AGILE trial, which initially opened in July 2019 and has screened over 1200 patients to date. Troriluzole and VT1021 will enroll patients with newly-diagnosed and recurrent glioblastoma.

Dr. Michael Lim, Chair of the Department of Neurosurgery at Stanford University and Dr. Michael Weller, Director Department of Neurology, University Hospital Zurich, Switzerland will serve as arm Principal Investigators for troriluzole’s evaluation in GBM AGILE. VT1021 will be led by arm Principal Investigators, Dr. Howard Colman, Professor, Huntsman Cancer Institute and Department of Neurosurgery, University of Utah, and Dr. Tom Mikkelsen, Medical Director, Precision Medicine Program & Clinical Trials Office, Henry Ford Health.

"GBM AGILE is a ground-breaking trial that enables us to simultaneously and dynamically study the effects of multiple new drug candidates in an optimized learning environment. The trial’s nimble model allows us to more efficiently and rapidly identify effective therapies for GBM patients," said Dr. Michael Lim, who also serves as a member of the GBM AGILE Arm Identification and Selection Committee. "We are excited to include troriluzole and VT1021 in GBM AGILE. These investigational drugs have the potential to support improved outcomes for GBM patients, who desperately need more effective treatment options."

GBM AGILE is an international, innovative platform trial designed to more rapidly identify and confirm effective therapies for patients with glioblastoma through response adaptive randomization and a seamless phase 2/3 design. The trial, conceived by over 130 key opinion leaders, is conducted under a master protocol, allowing multiple therapies or combinations of therapies from different pharmaceutical partners to be evaluated simultaneously. With its innovative design and efficient operational infrastructure, data from GBM AGILE can be used as the foundation for a new drug application (NDA) and biologics license application (BLA) submissions and registrations to the FDA and other health authorities.

The new interventions are opening first at Henry Ford Health Cancer in Detroit under Henry Ford site Principal Investigator Dr. Tom Mikkelsen and will subsequently open at more than 40 trial sites across the United States with additional global sites to follow.

"Glioblastoma is a devasting disease with few effective treatment options and no cure. Currently the average survival rate is estimated to be only eight months," noted Dr. Mikkelsen. "We are enthusiastic to be the first site to activate troriluzole and VT1021 in the GBM AGILE study. We are committed to finding our patients the best possible treatments."

Biohaven’s troriluzole is a novel, orally administered small molecule that modulates glutamate, the most abundant excitatory neurotransmitter in the human body. Troriluzole is thought to restore glutamate homeostasis by enhancing glutamate cycling, decreasing presynaptic glutamate release, and augmenting the expression and function of excitatory amino acid transporters (i.e., EAAT2) located on glial cells that play a key role in clearing excess glutamate from the synapse. Troriluzole was selected for inclusion in GBM AGILE, based on compelling evidence showing deregulation of glutamate in glioblastoma. The therapeutic potential of troriluzole in glioblastoma and other oncology indications is supported by several recent clinical and translational research studies conducted with troriluzole and its active moiety.

"The initiation of this pivotal trial of troriluzole for glioblastoma is an exciting milestone," commented Dr. Vlad Coric, Chairman and Chief Executive Officer of Biohaven. "We are extremely proud to be joining the highly innovative GBM AGILE trial. We look forward to collaborating with the Principal Investigators, Drs. Lim and Weller, the team at GCAR, and the GBM AGILE trial sites in order to rapidly advance the development of troriluzole in combination with standard of care therapies as a novel treatment for people suffering from glioblastoma, which is amongst the most recalcitrant and lethal of all cancers."

Vigeo’s VT1021, is a first-in-class dual modulating compound that blocks the CD47 immune checkpoint and activates the apoptotic and macrophage reprogramming activity of CD36. The result of the dual modulating activity is the induction of apoptosis in tumor and endothelial cells, as well as an increase in both CTL:Treg and M1:M2 macrophage ratio. The biological/therapeutic activity of VT1021 is mediated by the stimulation of thrombospondin-1 (Tsp-1). Through these dual-modulating effects VT1021 reprograms the tumor microenvironment from one that is immune suppressive, or "cold," to immune enhanced (or sensitized), or "hot," that are more susceptible to attack from the immune system. With its novel mechanism of action and clinical data from a Phase 2 expansion study in recurrent GBM patients, VT1021 is undergoing further studies to determine its effect in treating the disease, given that CD36 and CD47 are found to be highly expressed in tumor cells compared to normal brain tissue. Vigeo is developing VT1021 as a therapeutic agent across a range of cancers, with a current focus on solid tumors.

"VT1021 has seen remarkable patient response, with a great safety profile, in our earlier clinical trials. We are excited that VT1021 is included as part of this global, multi-site effort to treat such a devastating disease," said Jim Mahoney, Chief Executive Officer, Vigeo Therapeutics. "The opportunity to work with these distinguished Principal Investigators and to test our drug in both newly diagnosed and recurrent GBM patient populations are key factors in our decision to join AGILE."

On July 6, 2022 Genentech, a member of the Roche Group (SIX: RO, ROG; OTCQX: RHHBY), reported that the U.S. Food and Drug Administration (FDA) has accepted the company’s Biologics License Application (BLA) and granted Priority Review for mosunetuzumab, a potential first-in-class CD20xCD3 T-cell engaging bispecific antibody, for the treatment of adults with relapsed or refractory (R/R) follicular lymphoma (FL) who have received at least two prior systemic therapies (Press release, Genentech, JUL 6, 2022, View Source [SID1234616483]). FL is the most common indolent (slow growing) form of non-Hodgkin’s lymphoma (NHL), a type of blood cancer, which often returns after initial therapy. The FDA is expected to make a decision on approval of this novel cancer immunotherapy by December 29, 2022.

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"New therapeutic options are needed for follicular lymphoma, which often relapses after initial therapy and becomes increasingly difficult to treat each time it returns. Clinical trial results have demonstrated durable responses with mosunetuzumab in advanced follicular lymphoma, representing a step toward shifting the treatment paradigm"

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"New therapeutic options are needed for follicular lymphoma, which often relapses after initial therapy and becomes increasingly difficult to treat each time it returns. Clinical trial results have demonstrated durable responses with mosunetuzumab in advanced follicular lymphoma, representing a step toward shifting the treatment paradigm," said Levi Garraway, M.D., Ph.D., chief medical officer and head of Global Product Development. "Since mosunetuzumab does not require the collection or genetic modification of patient cells, it could become an effective, fixed-duration outpatient option without the barriers of travelling to a major academic center."

The BLA is based on positive results from the pivotal Phase I/II GO29781 study of mosunetuzumab, which showed high complete response (CR) rates, with the majority of responders (57% [95% CI: 49-70]) maintaining responses for at least 18 months, and manageable tolerability in people with heavily pretreated FL. After a median follow-up of 18.3 months, the CR rate was 60% (n=54/90) and the objective response rate was 80% (n=72/90). The median duration of response among those who responded was 22.8 months (95% CI: 9.7-not estimable). The most common adverse event (AE) was cytokine release syndrome (39%; n=86/218), which was generally low grade (grade 1: 25.6%; grade 2: 14%; grade 3: 2.3%; grade 4: 0.5%), and all events resolved. Other common AEs (>20%) included fatigue, headache, neutropenia, fever and hypophosphatemia. Treatment was administered without mandatory hospitalization. Results were presented for the first time in December 2021 at the 63rd American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting & Exposition.

Priority Review designation is granted to medicines that the FDA considers to have the potential to provide significant improvements in the safety and effectiveness of the treatment, prevention or diagnosis of a serious disease. The FDA granted Breakthrough Therapy Designation (BTD) to mosunetuzumab for the treatment of adults with R/R FL who have received at least two prior systemic therapies in June 2020 and Orphan Drug Designation in December 2018. BTD is designed to accelerate the development and review of medicines intended to treat serious or life-threatening conditions with preliminary evidence that indicates they may demonstrate substantial improvement over existing therapies. The European Commission granted conditional marketing authorization for mosunetuzumab for the treatment of people with R/R FL who have received at least two prior systemic therapies in June 2022.

A robust development program for mosunetuzumab is ongoing including two Phase III studies: CELESTIMO investigating mosunetuzumab plus lenalidomide in second-line plus (2L+) FL, and SUNMO, investigating mosunetuzumab plus Polivy (polatuzumab vedotin) in 2L+ diffuse large B-cell lymphoma (DLBCL).

About the GO29781 Study

The GO29781 study [NCT02500407] is a Phase I/II, multicenter, open-label, dose-escalation and expansion study evaluating the safety, efficacy and pharmacokinetics of mosunetuzumab in people with relapsed or refractory B-cell non-Hodgkin’s lymphoma. Outcome measures include complete response rate (best response) by independent review facility (primary endpoint), objective response rate, duration of response, progression-free survival, safety and tolerability (secondary endpoints).

About Follicular Lymphoma

Follicular lymphoma (FL) is the most common slow-growing (indolent) form of non-Hodgkin’s lymphoma, accounting for about one in five cases. It typically responds well to treatment but is often characterized by periods of remission and relapse. The disease typically becomes harder to treat each time a patient relapses, and early progression can be associated with poor long-term prognosis. In the United States, it is estimated that approximately 13,000 new cases of FL will be diagnosed in 2022.

About Mosunetuzumab

Mosunetuzumab is a first-in-class CD20xCD3 T-cell engaging bispecific antibody designed to target CD20 on the surface of B cells and CD3 on the surface of T cells. This dual targeting activates and redirects a patient’s existing T cells to engage and eliminate target B cells by releasing cytotoxic proteins into the B cells. A robust clinical development program for mosunetuzumab is ongoing, investigating the molecule as a monotherapy and in combination with other medicines, for the treatment of people with B-cell non-Hodgkin’s lymphomas, including follicular lymphoma, diffuse large B-cell lymphoma and other blood cancers.

About Polivy (polatuzumab vedotin-piiq)

Polivy is a first-in-class anti-CD79b antibody-drug conjugate (ADC). The CD79b protein is expressed specifically in the majority of B cells, an immune cell impacted in some types of non-Hodgkin’s lymphoma (NHL), making it a promising target for the development of new therapies. Polivy binds to CD79b and destroys these B cells through the delivery of an anti-cancer agent, which is thought to minimize the effects on normal cells. Polivy is being developed by Genentech using Seagen ADC technology and is currently being investigated for the treatment of several types of NHL.

Polivy U.S. Indication

Polivy is a prescription medicine used with other medicines, bendamustine and a rituximab product, to treat diffuse large B-cell lymphoma in adults who have progressed after at least two prior therapies.

The accelerated approval of Polivy is based on a type of response rate. There are ongoing studies to confirm the clinical benefit of Polivy.

Important Safety Information

Possible serious side effects

Everyone reacts differently to Polivy therapy, so it’s important to know what the side effects are. Some people who have been treated with Polivy have experienced serious to fatal side effects. A patient’s doctor may stop or adjust a patient’s treatment if any serious side effects occur. Patients must contact their healthcare team if there are any signs of these side effects.

Nerve problems in arms and legs: This may happen as early as after the first dose and may worsen with every dose. If a patient already has nerve pain, Polivy may make it worse. The patient’s doctor will monitor for signs and symptoms, such as changes in sense of touch, numbness or tingling in hands or feet, nerve pain, burning sensation, any muscle weakness, or changes to walking patterns
Infusion-related reactions: A patient may experience fever, chills, rash, breathing problems, low blood pressure, or hives within 24 hours of the infusion
Infections: Patients should contact their healthcare team if they experience a fever of 100.4°F or higher, chills, cough, or pain during urination. Also, a patient’s doctor may give medication before giving Polivy, which may prevent some infections, and monitor blood counts throughout treatment with Polivy. Treatment with Polivy can cause severe low blood cell counts
Rare and serious brain infections: A patient’s doctor will monitor the patient closely for signs and symptoms of these types of infections. Patients should contact their doctor if they experience confusion, dizziness or loss of balance, trouble talking or walking, or vision changes
Tumor lysis syndrome: Caused by the fast breakdown of cancer cells. Signs include nausea, vomiting, diarrhea, and lack of energy
Potential harm to liver: Some signs include tiredness, weight loss, pain in the abdomen, dark urine, and yellowing of the skin or the white part of the eyes. Patients may be at higher risk if they already have liver problems or are taking other medication
Side effects seen most often

The most common side effects during treatment were:

Low blood cell counts (platelets, red blood cells, white blood cells)
Nerve problems in arms and legs
Tiredness or lack of energy
Diarrhea
Nausea
Fever
Decreased appetite
Infections
Polivy may not be for everyone. A patient should talk to their doctor if they are:

Pregnant or may be pregnant: Data have shown that Polivy may harm an unborn baby
Planning to become pregnant: Women should avoid getting pregnant while taking Polivy. Women should use effective contraception during treatment and for at least 3 months after their last Polivy treatment. Men taking Polivy should use effective contraception during treatment and for at least 5 months after their last Polivy treatment
Breastfeeding: Women should not breastfeed while taking Polivy and for at least 2 months after the last dose
These may not be all the side effects. Patients should talk to their healthcare provider for more information about the benefits and risks of Polivy treatment.

On July 6, 2022 Enlivex Therapeutics Ltd. (Nasdaq: ENLV, the "Company"), a a clinical-stage macrophage reprogramming immunotherapy company targeting diseased macrophages in patients with sepsis and solid tumors, reported that the first patient has been dosed in a Phase I/II clinical trial evaluating Allocetra combined with chemotherapy in patients with peritoneal metastases arising from solid cancer (Press release, Enlivex Therapeutics, JUL 6, 2022, View Source [SID1234616504]).

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Peritoneal cancer, whether originating from a primary tumor within the peritoneum or from a metastatic tumor elsewhere in the body, is a terminal disease with a poor prognosis. Patients with peritoneal metastases are in urgent need of novel treatment options, as standard-of- care (SOC) chemotherapy currently provides only modest survival benefits. The median survival of patients with peritoneal metastases differs based on the location of the primary tumor but is frequently poor, with survival rates of 2.9 months, 6.5 months, and 6.9 months reported for cancers of pancreatic, gastric, and colorectal origins, respectively.

Prof. Aviram Nissan, M.D., Head of the Department of General and Oncological Surgery at Sheba Medical Center and Principal Investigator of the trial commented: "The patients are operated using the Pressurized Intra-Peritoneal Aerosol Chemotherapy (PIPAC) technology, which allows for efficient insertion of therapeutics directly to the peritoneum. We hope that the combination of chemotherapy and Allocetra, a next-generation cell therapy in development for oncological indications, will generate a breakthrough in the treatment of peritoneal metastases, which are not treatable in most patients with anti-cancer drugs available today. We are eager to test this new combination with the hope of changing the lives of patients with peritoneal metastases."

Mohammad Adileh, M.D., Attending Surgical Oncologist, Department of Surgery and Surgical Oncology – Surgery C, and a Co-Investigator in the trial stated: "Together with my team, I performed a ground breaking procedure in a patient with abdominal metastasis, combining a novel drug delivery system, PIPAC, with Allocetra, the development-stage macrophage-reprogramming cell therapy produced by Enlivex. I look forward to understanding the scope of the effect of Allocetra and its impact on the immune system in its efforts to recognize and kill malignant tumors in the abdomen. We are excited to test this combination as a new hope for patients with peritoneal cancers."

"The initiation of our first oncology trial is a crucial moment in Enlivex’s evolution," said Oren Hershkovitz, Ph.D., Chief Executive Officer of Enlivex. "We believe that it de-risks our pipeline with another avenue for value creation and positions us to substantially expand our addressable patient population. We look forward to the trial’s advancement and to expanding our oncology clinical program and would like to thank all those who helped achieve this important milestone."

Prof. Dror Mevorach, M.D., Chief Scientific Officer of Enlivex commented: "We believe that Allocetra has strong anti-cancer potential in a novel mechanism. Preclinical data suggests that Allocetra rebalances macrophage populations within the tumor microenvironment into a homeostatic state that favors anti-tumoral macrophages. This, in-turn, is expected to weaken the tumor defense mechanisms that limit the efficacy of currently available therapies. With this novel mechanism of action, Allocetra can potentially enhance the anti-cancer activity of a broad range of drug classes across a spectrum of highly prevalent solid cancers."

"Pro-tumor" tumor associated macrophages typically form a physical layer on top of solid cancers and induce an immunosuppressive tumor microenvironment. This promotes cancer growth and metastasis and limits the efficacy of anti-cancer agents, which ultimately contributes to poor clinical outcomes. Preclinical studies, including those that were recently featured at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting and the International Society for Cell and Gene Therapy Annual Meeting, suggest that Allocetra has the potential to synergistically combine with various anti-cancer agents to provide patients who do not respond well to existing FDA-approved therapies with an effective treatment option.

ABOUT THE PHASE I/II TRIAL

The Phase I/II trial is a company-sponsored, open-label, dose escalation and expansion trial that is expected to enroll a total of approximately 12 patients across four cohorts. It is designed to evaluate the safety and potential preliminary efficacy of Allocetra combined with SOC chemotherapy in patients with peritoneal metastases arising from solid cancer. The study will begin with two cohorts of intra-patient and intra-cohort dose escalation to determine the maximum feasible dose (MFD) of Allocetra in this population, followed by two additional cohorts comparing administration of Allocetra at the selected dose either before or after administration of SOC via a pressurized intraperitoneal aerosol chemotherapy procedure (PIPAC; a technique applied when patients are not eligible to receive the standard treatment due to a considerable tumor load, large quantities of persistent ascites, or other circumstances).

Intraperitoneally delivered Allocetra and SOC chemotherapy administered via PIPAC will be given to patients every six weeks. Systemic chemotherapy will also be administered per the treating oncologist’s plan. The primary endpoint is the number and severity of Allocetra-related adverse events and serious adverse events during the 16-week period, starting from the first administration of study treatment. Secondary endpoints include efficacy assessments, such as best overall response rate (ORR), progression-free survival, and overall survival. Changes from baseline in macrophage and immune cell characteristics in peritoneal fluid and tissues will also be assessed as an exploratory endpoint.

ABOUT ALLOCETRA

Allocetra is being developed as a universal, off-the-shelf cell therapy designed to reprogram macrophages into their homeostatic state. Diseases such as solid cancers, sepsis, and many others reprogram macrophages out of their homeostatic state. These non-homeostatic macrophages contribute significantly to the severity of the respective diseases. By restoring macrophage homeostasis, Allocetra has the potential to provide a novel immunotherapeutic mechanism of action for life-threatening clinical indications that are defined as "unmet medical needs", as a stand-alone therapy or in combination with leading therapeutic agents.