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Tmunity Announces First Patient Dosed in Phase 1 Clinical Trial with CART-TnMUC1

On January 15, 2020 Tmunity Therapeutics, Inc., a private clinical-stage biotherapeutics company focused on saving and improving lives by delivering the full potential of next-generation T-cell immunotherapy, reported that it has dosed the first patient in its Phase 1 CART-TnMUC1-01 clinical trial with the Tn/STn glycoform of mucin 1 (TnMUC1) chimeric antigen receptor T-cell (CAR-T) therapy in patients with TnMUC1-positive advanced cancers (Press release, Tmunity Therapeutics, JAN 15, 2020, View Source [SID1234553234]). This is a first-in-human trial with a CAR-T therapy targeting this antigen.

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The CART-TnMUC1 therapy was developed by a University of Pennsylvania (Penn) team led by Avery D. Posey, PhD, an assistant professor of pharmacology and a member of Penn’s Abramson Cancer Center. The MUC1 glycoprotein is a transmembrane epithelial mucin normally expressed on the apical surface of most simple glandular epithelial cells. In tumors that arise from these cells, an alternate form of MUC1 is frequently overexpressed on the cancer cell surface. The alternate form, known as TnMUC1, is depolarized and aberrantly glycosylated. Tmunity’s cell therapy specifically targets the Tn (GalNAca1-O-Ser/Thr) and sialyl-Tn (STn) (NeuAca2-6-GalNAcal-O-Ser/Thr) glycoforms of MUC1 with a fusion protein recognizing a short peptide sequence with one or two Tn O-glycans on the Ser/Thr residues. Tmunity’s CAR-T therapy also contains within its construct a novel co-stimulator region known as CD2.

"The initiation of the first trial to dose a patient with a CART-TnMUC1 represents an important milestone not only for Tmunity, but for the oncology community," said Usman "Oz" Azam, MD, President and Chief Executive Officer of Tmunity. "This clinical trial marks the third program from our portfolio to enter the clinical testing phase since our company was founded in 2015. We look forward to progressing our portfolio of innovative cell therapies for high unmet need in solid tumors and advancing the potential for CAR-T therapeutics."

"The major challenge in the field of CAR-T cells is targeting solid tumors, and we have great hope that we have potentially identified a new therapeutic approach," Posey said. "Our approach, testing these ‘sweet CARs,’ is to target a sugar that is uniquely expressed in tumor cells, with the aim to develop a more effective cancer therapy."

About the CART-TnMUC1-01 Phase 1 Trial

The CART-TnMUC1-01 study is a Phase 1 trial evaluating the investigational product CART-TnMUC1 in patients with TnMUC1 positive refractory tumors in combination with a lymphodepletion chemotherapy regimen. The primary objective of the trial is to establish safety and the recommended Phase 2 dose of CART-TnMUC1 that can be administered with lymphodepletion. The trial is currently open to patients with TnMUC1-positive, treatment-resistant solid tumors, including: metastatic ovarian cancer (including cancers of the fallopian tube), pancreatic ductal adenocarcinoma, hormone receptor (HR)-negative and HER2-negative (triple negative) breast cancer (TNBC) and non-small cell lung cancer. Please refer to www.clinicaltrials.gov for additional clinical trial information.

Iovance Biotherapeutics Completes Patient Dosing in Registration-Enabling Cohort 4 of the C-144-01 Melanoma Study with Lifileucel

On January 15, 2020 Iovance Biotherapeutics, Inc. (NASDAQ: IOVA), a late-stage biotechnology company developing novel T cell-based cancer immunotherapies, reported that the company has completed dosing the last patient in the registration-enabling Cohort 4 of the C-144-01 study of lifileucel in the treatment of patients with advanced melanoma (Press release, Iovance Biotherapeutics, JAN 15, 2020, View Source [SID1234553233]). Cohort 4 has the primary endpoint of objective response rate (ORR) to be read out by an Independent Review Committee.

"We are quite pleased to complete patient dosing of this pivotal cohort in our study of lifileucel ahead of schedule due to increased demand, bringing this potential therapy one step closer to patients," said Maria Fardis, Ph.D., MBA, Iovance President and Chief Executive Officer. "We remain on track to submit a Biologics License Application (BLA) subsequent to discussions with FDA, for regulatory approval of lifileucel in late 2020. Lifileucel could be the first approved cell therapy product for solid tumors."

Iovance Tumor Infiltrating Lymphocytes (TIL) for melanoma, lifileucel, is an investigational, patient-derived cell therapy that involves a 22-day manufacturing process at a centralized facility. Cohort 4 in the C-144-01 study includes post-PD-1 patients with Stage IIIC/IV unresectable melanoma who also have received BRAF/MEK therapy if clinically indicated. Lifileucel has been granted Regenerative Medicine Advanced Therapy (RMAT), Fast Track and Orphan Drug designations in advanced melanoma.

First Patient Dosed with Cellectis’ New Allogeneic UCART123 Product Candidate for Relapsed/Refractory Acute Myeloid Leukemia

On January 15, 2020 Cellectis (Euronext Growth: ALCLS – Nasdaq: CLLS), a clinical-stage biopharmaceutical company focused on developing immunotherapies based on gene-edited allogeneic CAR T-cells (UCART), reported the first patient dosing in AMELI-01, the Phase 1 dose escalation clinical trial evaluating a new UCART123 product candidate in relapsed/refractory acute myeloid leukemia (AML) (Press release, Cellectis, JAN 15, 2020, View Source [SID1234553232]). This trial, sponsored by Cellectis, is part of an Investigational New Drug (IND) from the US Food and Drug Administration for a new UCART123 construct and an optimized production process, and will evaluate the safety, expansion, persistence and clinical activity of the product candidate in patients with relapsed/refractory AML. AMELI-01 replaces the first US clinical trial assessing the UCART123 product candidate.

"Cellectis invented and has pioneered the allogeneic approach for many years," said Dr. André Choulika, Chairman and CEO, Cellectis. "Being a leader of the space, it’s important for us to consistently improve our technology and manufacturing expertise to remain at the forefront. With this new IND, we are delivering on our promise of continual innovation in order to advance the efforts of our clinical trials. We hope that with this optimized production process, our UCART123 product candidate will be well equipped to help people living with AML."

This clinical trial is led by Gail J. Roboz, M.D., Professor of Medicine at Weill Cornell Medicine and New York-Presbyterian (New York, USA), in collaboration with Naveen Pemmaraju, M.D., Associate Professor, Department of Leukemia, Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center (Texas, USA), David Sallman, M.D., Assistant Member in the Malignant Hematology Department at H. Lee Moffitt Cancer Center (Florida, USA), and Daniel DeAngelo, M.D., Ph.D., Institute Physician and Director of Clinical and Translational Research of Adult Leukemia at Dana Farber Cancer Institute (Massachusetts, USA).

About UCART123

Our wholly controlled product candidate, UCART123, is a gene-edited T-cell investigational drug that targets CD123, an antigen expressed at the surface of leukemic cells in AML. In July 2019, the US Food and Drug Administration (FDA) accepted an Investigational New Drug (IND) for Cellectis to conduct a Phase 1 clinical trial with an optimized version of the UCART123 product candidate in patients living with AML. This IND includes a new UCART123 construct and an optimized production process, and replaces our previous IND on UCART123.

Publication in Cancer Research demonstrates Crescendo Biologics’ Humabody® VH therapeutics outperform conventional antibodies in vivo

On January 15, 2020 Crescendo Biologics Ltd (Crescendo), the drug developer of novel, targeted, T cell enhancing therapeutics, reported the publication of a paper that demonstrates greater tissue penetration and in vivo efficacy of Humabody VH therapeutics compared to conventional antibody formats, in the scientific journal Cancer Research a journal of the American Association for Cancer Research (AACR) (Free AACR Whitepaper) (Press release, Crescendo Biologics, JAN 15, 2020, View Source [SID1234553230]).

The full paper by Nessler et al can be accessed online HERE.

The study run by Dr Greg M. Thurber at the University of Michigan demonstrates that the level of tissue penetration by Humabodies plays a major role in therapeutic efficacy and illustrates the benefits of using an albumin-binding domain to extend serum circulation time.

Humabodies are small, in vivo matured human VH domain building blocks that can be easily assembled into multifunctional molecules. They can be configured for optimal target engagement in ways which can be challenging for regular antibody formats. Dr Thurber’s results confirm that the smaller size and specifically tailored binding configuration achievable with Humabody molecules can result in improved penetration into the tumour microenvironment and a greater cancer-killing effect using a preclinical in vivo model of prostate cancer.

Dr Greg M. Thurber, an associate professor of chemical engineering and biomedical engineering at the University of Michigan, said:

"The tissue and cellular distribution of biologics is an important but understudied area in drug development. In collaboration with Crescendo, we demonstrated that the distribution of these drugs within the tumor was as significant as the total tumor dose in determining response. Importantly, this work shows how antibody engineering strategies can be used to design therapeutics with improved distribution to maximize efficacy."

Dr James Legg, SVP R&D at Crescendo Biologics, noted that:

"We’re delighted to be working with Greg Thurber’s team at the University of Michigan; they have developed a deep mechanistic understanding and expertise in the in vivo distribution of therapeutic agents. We look forward to continuing our collaboration."

Clovis Oncology’s Rubraca® (rucaparib) Granted FDA Priority Review for Advanced Prostate Cancer

On January 15, 2020 Clovis Oncology, Inc. (NASDAQ: CLVS) reported that the U.S. Food and Drug Administration (FDA) has accepted the company’s supplemental New Drug Application (sNDA) for Rubraca (rucaparib) and granted priority review status to the application with a Prescription Drug User Fee Act (PDUFA) date of May 15, 2020. Clovis submitted the sNDA submission for rucaparib as a monotherapy treatment of adult patients with BRCA1/2-mutant recurrent, metastatic castrate-resistant prostate cancer in November 2019 (Press release, Clovis Oncology, JAN 15, 2020, View Source [SID1234553229]).

"Recently presented data suggests that Rubraca may play a meaningful role in the treatment of patients withBRCA1/2-mutant recurrent, metastatic castrate-resistant prostate cancer, and this filing represents an important milestone for Clovis as it brings us one step closer to potentially making this valuable therapy available," said Patrick J. Mahaffy, President and CEO of Clovis Oncology. "We are encouraged by the FDA’s decision to grant priority review to the Rubraca application, which focuses on eligible patients with advanced prostate cancer, for whom new treatment options are very much needed."

A priority review designation is granted to proposed medicines that the FDA has determined have the potential, if approved, to offer a significant improvement in the safety or effectiveness of the treatment, prevention or diagnosis of a serious condition. Priority designation shortens the review period from the standard 10 months to six months.

About Prostate Cancer

The American Cancer Society estimated that more than 175,000 men in the United States would be diagnosed with prostate cancer in 2019, and the GLOBOCAN Cancer Fact Sheets estimated that approximately 450,000 men in Europe were diagnosed with prostate cancer in 2018. Castrate-resistant prostate cancer has a high likelihood of developing metastases. Metastatic castrate-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. According to the American Cancer Society, the five-year survival rate for mCRPC is approximately 30 percent. Up to 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.

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.

Rubraca U.S. FDA Approved Indications

Rubraca is indicated as monotherapy for the maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response to platinum-based chemotherapy.

Rubraca is indicated as monotherapy for the treatment of adult patients with deleterious BRCA mutations (germline and/or somatic) associated epithelial ovarian, fallopian tube, or primary peritoneal cancer who have been treated with two or more chemotherapies and selected for therapy based on an FDA-approved companion diagnostic for Rubraca.

Select Important Safety Information

Myelodysplastic Syndrome (MDS)/Acute Myeloid Leukemia (AML) occur uncommonly in patients treated with Rubraca, and are potentially fatal adverse reactions. In approximately 1100 treated patients, MDS/AML occurred in 12 patients (1.1%), including those in long-term follow-up. Of these, five occurred during treatment or during the 28-day safety follow-up (0.5%). The duration of Rubraca treatment prior to the diagnosis of MDS/AML ranged from 1 month to approximately 28 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. 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 (see Dosage and Administration [2.2] in full Prescribing Information) 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 cytogenetic analysis. If MDS/AML is confirmed, discontinue Rubraca.

Based on its mechanism of action and findings from animal studies, Rubraca can cause fetal harm when administered to a pregnant woman. Apprise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment and for 6 months following the last dose of Rubraca.

Most common adverse reactions in ARIEL3 (≥ 20%; Grade 1–4) were nausea (76%), fatigue/asthenia (73%), abdominal pain/distention (46%), rash (43%), dysgeusia (40%), anemia (39%), AST/ALT elevation (38%), constipation (37%), vomiting (37%), diarrhea (32%), thrombocytopenia (29%), nasopharyngitis/upper respiratory tract infection (29%), stomatitis (28%), decreased appetite (23%) and neutropenia (20%).

Most common laboratory abnormalities in ARIEL3 (≥ 25%; Grade 1–4) were increase in creatinine (98%), decrease in hemoglobin (88%), increase in cholesterol (84%), increase in alanine aminotransferase (ALT) (73%), increase in aspartate aminotransferase (AST) (61%), decrease in platelets (44%), decrease in leukocytes (44%), decrease in neutrophils (38%), increase in alkaline phosphatase (37%) and decrease in lymphocytes (29%).

Most common adverse reactions in Study 10 and ARIEL2 (≥ 20%; Grade 1–4) were nausea (77%), asthenia/fatigue (77%), vomiting (46%), anemia (44%), constipation (40%), dysgeusia (39%), decreased appetite (39%), diarrhea (34%), abdominal pain (32%), dyspnea (21%) and thrombocytopenia (21%).

Most common laboratory abnormalities in Study 10 and ARIEL2 (≥ 35%; Grade 1–4) were increase in creatinine (92%), increase in alanine aminotransferase (ALT) (74%), increase in aspartate aminotransferase (AST) (73%), decrease in hemoglobin (67%), decrease in lymphocytes (45%), increase in cholesterol (40%), decrease in platelets (39%) and decrease in absolute neutrophil count (35%).

Co-administration of Rubraca 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. Because of the potential for serious adverse reactions in breast-fed children from Rubraca, advise lactating women not to breastfeed during treatment with Rubraca and for 2 weeks after the last dose. You may report side effects to the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. You may also report side effects to Clovis Oncology, Inc. at 1-844-258-7662.