On September 28, 2017 CBT Pharmaceuticals (CBT), a biopharmaceutical company focused on developing innovative oncology therapeutics harnessing the immune system and targeting specific molecular pathways to tame cancer, reported that the first subject has been dosed in the Phase 1 multi-center study, CBT-101-01 (Press release, CBT Pharmaceuticals, SEP 28, 2017, View Source [SID1234520681]). CBT-101 is a specific oral inhibitor of the c-Met kinase. This is the company’s first clinical trial in the United States (NCT03175224). Following identification of a dose for CBT-101, the trial is planned to expand into tumor specific cohorts.

“This is an important milestone for CBT and its employees. We are also extremely grateful to the patients and clinical researchers at premier U.S. institutions that will contribute to the evaluation of CBT-101,” said Sanjeev Redkar, Ph.D., President and Chief Executive Officer. “CBT-101 has demonstrated strong inhibition of tumor growth in cell lines and patient derived models across multiple tumor types with c-Met fusions, mutations or amplifications. We anticipate the clinical results so that we can explore single agent development as well as combination approaches.”

“The aberrant activation of c-Met has been demonstrated to be highly correlated with outcome in many cancer indications, including kidney, lung, gastric, esophageal and brain cancer and plays a major role in cancer pathogenesis including tumor growth, angiogenesis and metastasis, as well as the suppression of cell death,” said Anthony El-Khoueiry, M.D., Associate Professor of Clinical Medicine and Phase 1 Program Director at USC Norris Comprehensive Cancer Center. “Through our research collaboration with CBT Pharmaceuticals and the cadre of investigators on this trial, we look forward to characterizing CBT-101 safety profile and dose, and defining a path for further development.”

CBT-101-01 Clinical Trial

This is a Phase 1, multi-center, open-label, 2-part Dose Escalation Segment with a Dose and Disease Expansion Cohort study to assess the safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy of CBT-101 monotherapy in subjects with advanced solid tumors with c-Met dysregulation. These findings will be used to establish a recommended Phase 2 dose for future clinical trials. A total of approximately 68 subjects will be enrolled.

There are two other Phase 1 trials with CBT-101 (PLB1001) ongoing in China – one in Met-positive Advanced Non-Small Cell Lung Cancer and the other in PTPRZ1-MET Fusion Gene Positive Recurrent High-Grade Gliomas.

More information on all trials is available at ClinicalTrials.gov.

CBT-101 Oral Capsule (PLB1001)

CBT-101 is a novel small molecule drug that targets the epithelial to mesenchymal transition (EMT) pathway that is dysregulated in several tumors. It is a specific inhibitor of the c-Met receptor. CBT-101 has demonstrated tumor inhibitory effect in a variety of human primary c-Met amplified gastric, hepatic, pancreatic and lung cancer xenograft animal models with c-Met fusions, mutations or amplifications (AACR, 2017).

On September 28, 2017 ERYTECH Pharma (Paris:ERYP) (ADR:EYRYY), a clinical-stage biopharmaceutical company developing innovative therapies by encapsulating therapeutic drug substances inside red blood cells, reported the determination of the recommended pivotal Phase 3 dosing from its U.S. Phase 1 dose escalation study with eryaspase (GRASPA) in first line treatment of adult ALL patients (Press release, ERYtech Pharma, SEP 28, 2017, View Source [SID1234520680]).

The U.S. Phase 1 study with eryaspase (GRASPA) is an open label dose escalation study evaluating the safety of eryaspase in combination with CALGB 8811 protocol for first line treatment of adult ALL patients. The study is performed at five clinical sites across the United States. Prof. Dr. Richard Larson, director of the Hematologic Malignancies Clinical Research Program at the University of Chicago, is the principal investigator of the study.

ERYTECH recently announced that all patients had been treated in the third dose escalation cohort of this Phase 1 study. The steering committee of the study reviewed the safety data of all three treatment cohorts and agreed to pursue further development at the dose level of 100 U/kg. This dose level had been previously recommended following ERYTECH’s Phase 2 study in elderly ALL patients. It is also the dose level used in the Phase 2b study in second line, metastatic pancreatic cancer, that recently reported positive efficacy and safety results, and in the ongoing Phase 2b study in AML, from which top-line results are expected by the end of this year.

In parallel with running an expansion cohort of this Phase 1 study at this recommended dose, ERYTECH will potentially initiate the steps toward the launch of a pivotal Phase 3 study in first line adult ALL patients at this dose level.

On September 28, 2017 bluebird bio, Inc. (Nasdaq: BLUE), a clinical-stage company committed to developing potentially transformative gene therapies for serious genetic diseases and T cell-based immunotherapies for cancer, reported the treatment of the first patient with relapsed/refractory multiple myeloma in a Phase 1 study of bb21217 (Press release, bluebird bio, SEP 28, 2017, View Source [SID1234520679]). bb21217 is an investigational chimeric antigen receptor T cell (CAR T) therapy targeting B cell maturation antigen (BCMA). bluebird bio is developing bb21217 in collaboration with Celgene Corporation. bluebird bio also announced today that Celgene has exercised its option to exclusively license bb21217, under the terms of the collaboration between the two companies.

“bb21217, bluebird’s second oncology program to enter the clinic, complements bb2121, which has demonstrated encouraging safety and efficacy results in an ongoing Phase 1 trial. With bb21217, we manufacture a CAR T cell product enriched for ‘memory T cells’ – a long-lived, more potent T cell subtype – which in preclinical in vivo studies has shown improved anti-tumor activity,” said Philip Gregory, chief scientific officer, bluebird bio. “While the clinical data we have shared to date from our bb2121 program have shown deep and durable responses, we know that multiple myeloma is an aggressive and historically incurable cancer. With our partners at Celgene, we are excited to bring forward a second program reflecting our commitment to exploring all avenues to deliver cutting edge therapies to patients.”

“The advancement of bb21217 into the clinic builds upon the success of our first-generation program and is one more testament to bluebird’s and Celgene’s combined leadership in the field of anti-BCMA CAR T therapies,” said Rupert Vessey, EVP and President, Global Research & Early Development, Celgene. “We look forward to our continued partnership with bluebird to unleash the full potential of anti-BCMA CAR T therapies for patients living with historically incurable cancers.”

The bluebird bio and Celgene collaboration focuses on developing product candidates targeting BCMA for the treatment of patients with multiple myeloma. By exercising its exclusive option under the terms of the collaboration, Celgene will be responsible for worldwide development and commercialization of bb21217 after Phase 1. bluebird bio is responsible for the development of bb21217 through the completion of the CRB-402 Phase 1 study and has an option to share in the development, promotion and profits in the United States. bluebird bio will receive a $15 million option exercise payment from Celgene, and bluebird bio is also eligible to receive specified development, regulatory and commercial milestone payments and royalty payments on net sales.

About the CRB-402 Study
The primary objective of the CRB-402 study is to evaluate the maximum tolerated dose of bb21217 and determine the recommended Phase 2 dose. The secondary objective is preliminary efficacy data, measured using the International Myeloma Working Group (IMWG) Response Criteria for Multiple Myeloma. The first portion of the study includes a dose-escalation phase in which cohorts of patients will receive ascending doses of bb21217 to determine the maximum tolerated dose and establish a recommended Phase 2 dose. The second portion of the study is a dose expansion phase where patients will receive bb21217 to further evaluate the safety, tolerability and clinical activity at the recommended Phase 2 dose.

On September 28, 2017 BeiGene, Ltd. (NASDAQ:BGNE), a commercial-stage biopharmaceutical company focused on developing and commercializing innovative molecularly targeted and immuno-oncology drugs for the treatment of cancer, today presented preliminary data from the dose-verification portion of the ongoing Phase 1/2 trial of its investigational anti-PD-1 antibody BGB-A317 in Chinese patients with advanced solid tumors at the 20th Annual Meeting of the Chinese Society of Clinical Oncology (CSCO) in Xiamen, China (Press release, BeiGene, SEP 28, 2017, View Source [SID1234520678]). The preliminary data suggest that BGB-A317 was generally well tolerated and exhibited preliminary evidence of anti-tumor activity in a Chinese study population with advanced solid tumors. BeiGene and Celgene Corporation have a global strategic collaboration for BGB-A317 for solid tumors; BeiGene retains exclusive rights to BGB-A317 in China.

“BGB-A317 was generally well tolerated and showed preliminary activity in a heavily pretreated study population with advanced solid tumors. At the time of the data cut-off, no dose-limiting toxicities were observed. The pharmacokinetic profile in Chinese patients was consistent with that reported in global trials of BGB-A317 at the registrational dose,” commented Professor Lin Shen of the Peking University Cancer Hospital and Beijing Institute for Cancer Research, Beijing, China, the lead author of the abstract.

“This dose-verification trial is an important step as we advance BGB-A317 along China’s domestic innovative drug development pathway. Two registrational trials of BGB-A317, in urothelial cancer and classical Hodgkin lymphoma, are currently ongoing in China. The Celgene partnership allows us to increase our investment in BGB-A317, and we intend to initiate Phase 3 trials supporting approval in China for each of the four most common tumors in the country including lung, stomach, liver, and esophageal cancers, with the initial studies expected to start in the fourth quarter of 2017 or first quarter of 2018,” commented Amy Peterson, MD, Chief Medical Officer, Immuno-oncology at BeiGene.

Summary of Results from the Ongoing Phase 1/2 Trial

The multi-center Phase 1/2 trial of BGB-A317 consists of a Phase 1 dose-verification portion and a Phase 2 portion of indication expansion in disease-specific cohorts. Data presented at CSCO include patients enrolled in the Phase 1 portion of this study, who received BGB-A317 at 200 mg once every three weeks (Q3W).

As of June 16, 2017, 20 patients had enrolled in the trial. The median duration of therapy in these patients was 53 days (range 21–171 days).

Adverse events (AEs) assessed by the investigator to be related to treatment occurred in 19 patients (95%). The most common treatment-related AEs (TRAEs) were related to changes in clinical laboratory value; TRAEs occurring in 15% or more of patients included increased blood bilirubin (45%), anemia (35%), proteinuria (30%), increased aspartate transferase (AST) (25%), increased alanine transferase (ALT) (20%), leukopenia (15%), neutropenia (15%), pyrexia (15%), and vomiting (15%). All of the TRAE cases were grades 1 or 2 except for one case each of grade 3 increased blood bilirubin, leukopenia, and neutropenia. Increased AST (25%) and ALT (20%) were the most common AEs that were potentially immune related.

At the time of the data cutoff, 11 patients had at least one post-baseline imaging assessment, and three patients had at least two imaging assessments. The efficacy-evaluable population (measurable disease at baseline and at least one post-baseline tumor assessment, or progression or death) consisted of 12 patients, including three patients with microsatellite-instability-high (MSI-high) colorectal cancer (CRC), two patients with gastric cancer (GC), two patients with hepatocellular carcinoma (HCC), two patients with urothelial cancer (UC), two patients with melanoma, and one patient with gastrointestinal stromal tumor (GIST). Partial responses (PR) were observed in one patient with UC (confirmed) and one with GC (unconfirmed). Stable disease was observed in two patients with melanoma and one with MSI-high CRC. In the remaining eight patients who were not evaluable as of the data cutoff, a third unconfirmed PR was observed in a patient with esophageal cancer 11 days after the data cutoff. At the time of the data cutoff, 15 patients remained on treatment.

About BGB-A317

BGB-A317 is an investigational humanized monoclonal antibody that belongs to a class of immuno-oncology agents known as immune checkpoint inhibitors. It is designed to bind to PD-1, a cell surface receptor that plays an important role in downregulating the immune system by preventing the activation of T-cells. BGB-A317 has high affinity and specificity for PD-1. It is differentiated from the currently approved PD-1 antibodies in an engineered Fc region, which is believed to minimize potentially negative interactions with other immune cells. BGB-A317 is being developed as a monotherapy and in combination with other therapies for the treatment of a broad array of both solid tumor and hematologic cancers. BeiGene and Celgene Corporation have a global strategic collaboration for BGB-A317 for solid tumors.

On September 28, 2017 Galena Biopharma, Inc. (NASDAQ:GALE), a biopharmaceutical company developing hematology and oncology therapeutics that address unmet medical needs, reported that two clinical trials evaluating NeuVax (nelipepimut-S) in combination with trastuzumab (Herceptin; Genentech/Roche) for the prevention of recurrence in breast cancer patients have enrolled the protocol-defined number of patients to complete enrollment (Press release, Galena Biopharma, SEP 28, 2017, View Source [SID1234520677]). The milestones were reported by the clinical research organization conducting both trials – a Phase 2b clinical trial in HER2 1+/2+ patients and a Phase 2 clinical trial in HER2 3+ patients.

“Completing enrollment in both of these trials represents a major milestone for NeuVax development,” said Bijan Nejadnik, M.D., Executive Vice President and Chief Medical Officer of Galena. “The combination of trastuzumab and NeuVax has been shown to be synergistic in preclinical investigation, and we believe could be an effective treatment to prevent breast cancer recurrence in patients with no other treatment options. We would like to thank our investigators and patients who are participating in these trials as we look forward to the interim results next year for the Phase 2b trial and the primary endpoints for both trials in 2019.”

Phase 2b Clinical Trial in HER2 1+/2+ Patients

The Phase 2b clinical trial has enrolled the necessary 300 patients to complete enrollment. The clinical trial is a randomized, multicenter, investigator-sponsored, study enrolling HER2 1+ and 2+, HLA A2+, A3+, A24 and/or A26, node positive, and high-risk node negative breast cancer patients. Eligible patients are randomized to receive NeuVax + GM-CSF + trastuzumab or trastuzumab + GM-CSF alone. Once enrolled, all patients receive the standard trastuzumab dosing for 12 months. One cohort also receives six doses of NeuVax given as a primary vaccine series starting with the third dose of trastuzumab and then goes on to receive a NeuVax booster inoculation once every six months for up to 36 months. The next milestone for the trial will be the interim efficacy analysis that is scheduled to be performed by the Data Safety Monitoring Board (DSMB) in the first quarter of 2018. The primary endpoint of the study is disease-free survival after 24 months, with results expected from that milestone in the fourth quarter of 2019. Genentech/Roche is providing the trastuzumab and partial funding for this trial.

Data presented in October 2016 demonstrated that this novel combination of trastuzumab and NeuVax with HER2 low-expressing patients is well tolerated and the cardiac effects of trastuzumab are not impacted by the addition of NeuVax. In February 2017, the DSMB reported that there were no safety concerns with the trial and the trial is not futile. The recommendation from the DSMB was to continue the trial with one revision to the statistical analysis plan regarding the timing of the pre-specified interim analysis. Given the lengthy duration of enrollment for the trial, the DSMB determined that the pre-specified interim efficacy analysis be moved up from 12 months to 6 months after the last patient is enrolled. Therefore, the DSMB expects to perform the interim efficacy analysis in the first quarter of 2018.

Phase 2 Clinical Trial in HER2 3+ Patients

The Phase 2 clinical trial has enrolled the necessary 100 patients to complete enrollment. This multi-center, prospective, randomized, single-blinded trial enrolled patients with a diagnosis of HER2 3+ breast cancer who are HLA A2+ or HLA A3+ and are determined to be at high-risk for recurrence. High-risk is defined as having received neoadjuvant therapy with an approved regimen that includes trastuzumab but not obtaining a pathological complete response at surgery, or underwent surgery as a first intervention and was found to be pathologically node-positive (≥ 4 positive lymph nodes, or having 1-3 positive lymph nodes (pN1) if hormone receptor negative). These high-risk patients are known to have higher recurrence rates than other HER2 3+ breast cancer patients. Eligible patients are randomized to receive NeuVax + GM-CSF + trastuzumab or trastuzumab + GM-CSF alone. Once enrolled, all patients receive the standard trastuzumab dosing for 12 months. One cohort also receives six doses of NeuVax given as a primary vaccine series starting with the third dose of trastuzumab and then goes on to receive a NeuVax booster inoculation once every six months for up to 36 months. The primary endpoint of the study is disease-free survival after 24 months, with results expected from that milestone in the fourth quarter of 2019. Partial funding for this trial was awarded through the Congressionally Directed Medical Research Program funded through the Department of Defense, via a Breast Cancer Research Program Breakthrough Award.

In February 2017, the DSMB reported that there were no safety concerns with the trial and the trial is not futile. The pre-specified interim safety analysis was completed on n=50 patients and demonstrated that the agent is well tolerated with no increased cardiotoxicity associated with giving NeuVax in combination with trastuzumab. The recommendation from the DSMB was to continue the HER2 3+ trial unmodified.

About NeuVax (nelipepimut-S)

NeuVax (nelipepimut-S) is a first-in-class, HER2-directed cancer immunotherapy under evaluation to prevent breast cancer recurrence after standard of care treatment in the adjuvant setting. It is the immunodominant peptide derived from the extracellular domain of the HER2 protein, a well-established target for therapeutic intervention in breast carcinoma. The nelipepimut-S sequence stimulates specific CD8+ cytotoxic T lymphocytes (CTLs) following binding to specific HLA molecules on antigen presenting cells (APC). These activated specific CTLs recognize, neutralize and destroy, through cell lysis, HER2 expressing cancer cells, including occult cancer cells and micrometastatic foci. The nelipepimut-S immune response can also generate CTLs to other immunogenic peptides through inter- and intra-antigenic epitope spreading. In clinical studies, NeuVax is combined with recombinant granulocyte macrophage-colony stimulating factor (GM-CSF).

NeuVax is currently in two breast cancer studies in combination with trastuzumab (Herceptin; Genentech/Roche): a Phase 2b trial in node positive and triple negative HER2 IHC 1+/2+ (clinicaltrials.gov identifier: NCT01570036); and, a Phase 2 trial in high risk, node positive or negative HER2 IHC 3+ patients (clinicaltrials.gov identifier: NCT02297698). A Phase 2 clinical trial is also ongoing with NeuVax in patients with ductal carcinoma in situ (DCIS) (clinicaltrials.gov identifier: NCT02636582), and a Phase 2 trial is planned in patients with gastric cancer.

About Breast Cancer

New cases of breast cancer occur at an annual rate of 125 per 100,000 women in the U.S., with over 250,000 new cases and 40,000 deaths expected in 2017. Approximately 89.7% of breast cancer patients are expected to survive five years after diagnosis. Approximately 12.4% of women will be diagnosed with breast cancer at some point during their lifetime (2011 – 2013 data). The prevalence data from 2013 showed an estimated 3,053,450 women living with breast cancer in the United States.

According to the National Cancer Institute (NCI), only about 25% of breast cancers diagnosed are HER2 positive (IHC 3+). NeuVax targets approximately 50%-60% of these women who are HER2 low to intermediate (IHC 1+/2+ or FISH < 2.0) and achieve remission with current standard of care, but have no available HER2-targeted adjuvant treatment options to maintain their disease-free status. Sources: National Cancer Institute and NCI Surveillance, Epidemiology, and End Results Program