ASCO Abstract #
Tepotinib (c-Met kinase inhibitor): 9082, 9016; M7824 (TGF-ß trap/anti-PD-L1): 3007, 9017, 2566; M2698 (dual p70S6k/Akt inhibitor): 2584; M6620 (ATR inhibitor): 2549; M3814 (DNA-PK):2518

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

Data from an ongoing Phase II tepotinib study show anti-tumor clinical activity in patients with advanced non-small cell lung cancer harboring MET exon 14 skipping mutations
Patients with advanced lung cancer harboring MET exon 14 mutations currently have a poor prognosis and limited treatment options
Safety data are consistent with data previously reported, with no new safety signals identified

Merck KGaA, Darmstadt, Germany, a leading science and technology company which operates its healthcare business in the U.S. and Canada as EMD Serono, reported that the investigational, targeted therapy tepotinib[*] has shown clinical activity in an ongoing Phase II study of patients with advanced non-small cell lung cancer (NSCLC) harboring MET exon 14 skipping mutations. Data from the VISION trial will be presented during the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) 2018 Annual Meeting in Chicago, June 1-5, 2018 (Press release, Merck KGaA, JUN 3, 2018, View Source [SID1234527388]).

"Patients living with advanced non-small cell lung cancer harboring MET exon 14 skipping mutations have limited treatment options available to them and typically face poor clinical outcomes," said investigator Enriqueta Felip, M.D., Medical Oncologist, Vall d’Hebron Institute of Oncology (VHIO). "More than half of the patients in the Phase II VISION study had an investigator-assessed confirmed response, demonstrating the potential of tepotinib and the need to further evaluate this precision medicine option."

Initial data from the Phase II VISION study of tepotinib in patients living with advanced NSCLC harboring MET exon 14 skipping mutations will be presented today at ASCO (Free ASCO Whitepaper) during the "Lung Cancer-Non-Small Cell Metastatic" poster discussion session, 11:30 a.m. – 12:45 p.m. CDT. Treatment with tepotinib led to a confirmed complete response (CR) or confirmed partial response (PR) in 53.6% (15/28) and stable disease (SD) in 17.9% (5/28) of patients based on investigator assessment. Based on independent assessment of updated data from 28 patients (patients with at least 2 post-baseline assessments or who discontinued for any reason), 42.9% (12/28) had a PR and 21.4% (6/28) had SD.

In this ongoing study, the safety data are consistent with that observed in previous studies; no new safety signals have been identified to date. A total of 26 out of 38 patients with data available experienced treatment-related adverse events (TRAEs), most commonly Grade 1/2 peripheral edema (13 patients) and diarrhea (10 patients). Seven patients reported Grade 3 TRAEs, including asymptomatic amylase increase (2 patients) and one instance each of: asthenia, generalized edema, aspartate aminotransferase increase, gamma-glutamyl transferase increase, lipase increase, hyperkalemia, dizziness and pneumonia. Four patients experienced serious TRAEs, with one instance of pneumonia, generalized edema, asthenia and dizziness, and interstitial lung disease. The VISION study is continuing to enroll patients harboring MET exon 14 skipping mutations from Europe, United States and Japan.

"These data support our plans to continue with the clinical development of tepotinib in this particularly aggressive, advanced lung cancer. Patients with this form of non-small cell lung cancer currently have a poor prognosis and limited treatment options," said Luciano Rossetti, M.D., Executive Vice President, Global Head of Research & Development at the biopharma business of Merck KGaA, Darmstadt, Germany. "Tepotinib is an important late-stage investigational therapy and a key part of our strategic focus on innovative precision medicines."

Tepotinib, discovered in-house at Merck KGaA, Darmstadt, Germany, is an investigational inhibitor of the c-Met receptor tyrosine kinase. Alterations of the c-Met signaling pathway are found in various cancer types and correlate with aggressive tumor behavior and poor clinical prognosis. Tepotinib has been designed with the potential to improve outcomes in aggressive tumors that have a poor prognosis and harbor these specific mutations. In March, the Japanese Ministry of Health, Labour and Welfare granted SAKIGAKE ‘fast-track’ designation to tepotinib in patients with NSCLC harboring MET exon 14 skipping mutations.

Presentation Date
Title Lead Author Abstract # / Time (CDT) Location

Tepotinib
Poster Sessions
Can duration of
response be used
as a surrogate
endpoint for
overall survival
in advanced
non-small cell Boris M Sun, Jun 03, 8:00
lung cancer? Pfeiffer 9082 a.m. – 11:30 a.m. Hall A
Poster Discussion
Tepotinib in
patients with
advanced
non-small cell
lung cancer
(NSCLC) harboring
MET exon
14-skipping
mutations: Phase Enriqueta Sun, Jun 03, 11:30
II trial. Felip, M.D. 9016 a.m. – 12:45 p.m. Arie Crown Theater

In addition to tepotinib, Merck KGaA, Darmstadt, Germany, is sharing data from across its oncology and immuno-oncology pipeline at ASCO (Free ASCO Whitepaper) 2018, including investigational immunotherapy M7824 and updates from its DNA Damage Response portfolio. Merck KGaA, Darmstadt, Germany, is committed to exploring an array of targets and taking creative scientific approaches to developing novel therapies for hard-to-treat cancers.

*Tepotinib is the recommended International Nonproprietary Name (INN) for the c-Met kinase inhibitor (MSC 2156119J). Tepotinib is currently under clinical investigation and not approved for any use anywhere in the world.

About Non-Small Cell Lung Cancer

Globally, lung cancer is the most common cause of cancer-related deaths in men and the second most common in women,[1] responsible for more deaths than colon, breast and prostate cancer combined.[2] NSCLC is the most common type of lung cancer, accounting for 80 to 85% of all lung cancers.[3] MET exon 14 skipping mutations occur in 3-4% of lung cancers.[5],[6] The five-year survival rate for people diagnosed with lung cancer that has spread (metastasized) to other areas of the body is 1%.[4]

About Tepotinib

Tepotinib is an investigational, small-molecule inhibitor of the c-Met receptor tyrosine kinase discovered in-house at Merck KGaA, Darmstadt, Germany. Alterations of the c-Met signaling pathway are found in various cancer types and correlate with aggressive tumor behavior and poor clinical prognosis. Tepotinib is currently being investigated in a Phase II study in NSCLC.

About SAKIGAKE

SAKIGAKE designation is granted by the Japanese Ministry of Health, Labour and Welfare, promoting research and development in Japan and aiming at early practical application for innovative pharmaceutical products, medical devices and regenerative medicines. SAKIGAKE designation can reduce a drug’s review period down from 12 months to a target of 6 months.

The system’s objective is to designate drugs that have the potential of prominent effectiveness against serious and life-threatening diseases in order to make them available to patients in Japan ahead of the rest of the world.

All Merck KGaA, Darmstadt, Germany, press releases are distributed by e-mail at the same time they become available on the EMD Group Website. In case you are a resident of the USA or Canada please go to View Source to register again for your online subscription of this service as our newly introduced geo-targeting requires new links in the email. You may later change your selection or discontinue this service.

On June 3, 2018 Polaris Group reported results from a phase 1 clinical study, showing that Polaris lead therapeutic candidate ADI‑PEG 20 in combination with FOLFOX demonstrated promising efficacy for heavily pre-treated hepatocellular carcinoma (HCC) patients (Press release, Polaris Pharmaceuticals, JUN 3, 2018, View Source [SID1234527209]). The results were presented by Dr. James Harding from Memorial Sloan Kettering Cancer Center at the American Society Clinical Oncology’s 2018 annual meeting.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

Overall, 38 HCC patients who have failed at least one line of prior systemic treatment were enrolled and a partial response (PR) was observed in 8 (21.0%), including two in Taiwan. Of the 38, 21 had failed at least two lines of prior systemic treatment, and PRs were observed in 5/21 (23.8%). Currently, all 5 of the third-line or later PR patients are still alive, with 4 of 5 still undergoing treatment and 2 having now maintained a PR for over two years; thus suggesting responses can potentially be durable.

Side effects of the combination have been what would be expected for FOLFOX only, except for injection site reactions consistent with ADI‑PEG 20’s intramuscular route of administration.

Given these encouraging results, a meeting was held with the United States Food & Drug Administration (FDA). Based on this meeting, the study has been expanded into a global, phase 2, single-arm study to support accelerated approval for HCC patients who have failed at least two lines of prior systemic therapies. This study is currently enrolling patients in the US and Taiwan, and will be expanded into UK, Italy, Korea and China.

"ADI‑PEG 20 plus FOLFOX is showing more favorable efficacy compared to historic controls and the combination remains well tolerated. We appreciate the helpful comments of the FDA in assisting us to craft the phase 2 portion of this protocol", said John Bomalaski, M.D., Executive Vice President, Medical Affairs, of Polaris. "We now have a number of clinical trials underway with ADI‑PEG 20 in combination with standard of care agents in multiple cancer indications. These other studies have also shown that ADI‑PEG 20 in combination with multiple chemotherapy agents is well tolerated, and highly improves response rates. We are committed to developing an effective treatment for the 3rd-line or later HCC patients who have no approved treatment option", he added.

About ADI‑PEG 20

ADI‑PEG 20 is a biologic being developed by Polaris Group to treat cancers carrying a major metabolic defect that renders them unable to internally synthesize arginine. Because arginine is essential for protein synthesis and survival of cells, these cancer cells become dependent upon the external supply of arginine to survive and grow. ADI‑PEG 20 is designed to deplete the external supply of arginine, causing arginine-dependent cancer cells to die while leaving the patient’s normal cells unharmed. Multiple cancers have been reported to have a high degree of arginine-dependency and can potentially be treated with ADI‑PEG 20.

On June 3, 2018 Forty Seven, Inc., a clinical-stage, immuno-oncology company focused on developing therapies to activate macrophages in the fight against cancer, reported proof-of-concept data from two separate clinical trials of 5F9: an ongoing Phase 1b/2 trial evaluating 5F9 in combination with rituximab in patients with relapsed/refractory non-Hodgkin’s lymphoma (r/r NHL) and a Phase 1 pharmacokinetic (PK) and pharmacodynamic (PD) trial in patients with advanced solid tumors (Press release, Forty Seven, JUN 3, 2018, View Source [SID1234527178]). 5F9 is a monoclonal antibody against CD47, which is designed to block the "don’t eat me" signal used by cancer cells to avoid being ingested by macrophages. The data are being presented in two oral presentations at the 2018 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting in Chicago, Illinois, June 1-5, 2018.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

"We are pleased to present the first-in-human data for 5F9, which support our belief in the value of harnessing macrophages to fight difficult-to-treat cancers, and help validate our molecule selection strategy and the potential of our proprietary prime-maintenance dosing regimen to overcome the toxicity limitations of previously tested anti-CD47 antibodies," said Chris Takimoto, M.D., Ph.D., F.A.C.P., Chief Medical Officer of Forty Seven, Inc. "Together, the data presented at ASCO (Free ASCO Whitepaper) reveal an encouraging clinical profile for 5F9, suggesting that blocking CD47 can render difficult-to-treat tumors susceptible to phagocytosis. We are particularly encouraged by the evidence of anti-tumor activity observed in patients with r/r NHL and advanced, relapsed ovarian cancer, who are refractory to, or unfit for, existing therapeutic options. We are committed to exploring 5F9’s full potential and are now advancing a broad clinical development program at the recommended priming and Phase 2 dose and schedule, including multiple trials across a range of tumors and treatment modalities."

Data from the Phase 1b Portion of the Ongoing Phase 1b/2 Trial of 5F9 in Combination with Rituximab in r/r NHL

Forty Seven’s Phase 1b/2 trial is designed to evaluate 5F9 in combination with rituximab in patients with r/r NHL, including patients with diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL). In the Phase 1b portion of the trial, patients received a 1 mg/kg priming dose of 5F9 to mitigate on-target anemia, followed by full doses of rituximab and escalating doses of 5F9, ranging from 10 mg/kg once weekly to 30 mg/kg once weekly. As of the data cutoff of April 2018, 22 patients had been treated across all dose groups in the Phase 1b portion of the trial, including 15 patients with DLBCL and seven patients with FL. Before dosing, 95% of patients were considered refractory to a prior rituximab regimen and the median number of prior therapies was four (ranging from two to 10).

Safety Data: As of the data cutoff date of April 2018, 5F9 was observed to be generally well-tolerated at all doses and the maximum tolerated dose was not defined with 5F9 dosing up to 30 mg/kg. The majority of adverse events (AEs) reported by investigators were Grade 1 or 2 and the most common treatment-related AEs were expected CD47-mechansim-based effects on red blood cells (RBC), which led to a temporary and reversible anemia. Other commonly reported AEs reported included chills, headache, infusion-related reaction and pyrexia. Only one patient discontinued due to an AE.

Clinical Data: As of the data cutoff date, 22 patients across all dose groups were evaluable for response assessment, including 15 patients with DLBCL and seven patients with FL. PET/CT imaging was used to measure clinical activity by the Lugano criteria, which include measures of tumor size and metabolic activity. Across all 22 evaluable patients, the data showed an objective response rate (ORR) of 50% and a complete response rate (CR) of 36%.

In DLBCL, the ORR was 40%, with 33% of patients achieving a CR.
In FL, the ORR was 71%, with 43% of patients achieving a CR.
Among all responding patients, only one patient has subsequently progressed with a median follow-up of over six months. A median duration of response has not been reached for either the DLBCL or FL patient populations, with a median follow-up of 6.2 months and 8.1 months for DLBCL and FL patients, respectively.

"Despite recent advancements, there remains a paucity of safe and effective therapies for patients with r/r NHL, especially for patients who are ineligible for transplantation or new cell therapies," said Sonali Smith, M.D., Elwood V. Jensen Professor in Medicine, an investigator for the study. "These preliminary data suggest that 5F9 may offer patients with DLBCL and FL a new treatment option that is both safe and easy to administer, and that can rapidly induce benefit, with a majority of responding patients showing clinical activity at first assessment with several complete remissions, despite being refractory to multiple prior regimens. I am excited to continue evaluating 5F9 in the Phase 2 portion of this trial, as we learn more about the clinical utility of this potentially transformative agent."

Data from the Phase 1 PK and PD Trial Evaluating 5F9 as a Single-Agent in Advanced Solid Tumors

Forty Seven’s Phase 1 trial was designed to evaluate the safety and tolerability of 5F9 and to define a recommended dose and schedule. A total of 62 patients were treated in the Phase 1 trial. This included 11 patients treated in Part A at four escalating priming doses (ranging from 0.1 mg/kg to 3 mg/kg once weekly); 14 patients treated in Part B at a priming dose of 1 mg/kg and three escalating maintenance doses (ranging from 3 mg/kg to 20 mg/kg once weekly); 15 patients treated in a tumor biopsy cohort at a priming dose of 1 mg/kg and a maintenance dose of 20 mg/kg; and 22 patients treated in Part C at a priming dose of 1 mg/kg and three escalating loading and maintenance doses (ranging from 20 mg/kg to 45 mg/kg once weekly). The treated patients had advanced tumors including colorectal, ovarian, salivary, breast and other solid tumors and were heavily pre-treated, with a median of five prior systemic treatments.

PK and PD: In Part A, 1 mg/kg was identified as the optimal priming dose sufficient to saturate CD47 on RBCs and trigger a compensatory reticulocytosis to mitigate the expected anemia due to the removal of older RBCs. PK data showed that 5F9 can overcome the CD47 antigen sink at doses of 10 mg/kg or higher, with free plasma drug levels exceeding the expected therapeutic range based on preclinical results. PK data at saturating dose levels also showed a mean half-life of approximately 13 days, supporting a maintenance dose once every two weeks. The Recommended Phase 2 Dose (RP2D) has been defined as a 1 mg/kg priming dose, followed by 30 mg/kg once weekly for three weeks, followed by a maintenance dose of 30 mg/kg every two weeks.

Safety Data: 5F9 was observed to be generally well-tolerated at all doses and the maximum tolerated dose was not defined up to 45 mg/kg. The majority of AEs reported by investigators were Grade 1 or 2. The most common treatment-related AEs were expected CD47-mechanism-based effects on RBC, including a predictable and frequently transient anemia that was successfully mitigated by Forty Seven’s priming and maintenance dosing regimen. Other frequently reported treatment-related AEs included infusion-site reactions, headache, fatigue, chills, fever and nausea, which were generally mild-to-moderate in severity and easily managed.

Clinical Data: Preliminary evidence of anti-tumor activity with single-agent 5F9 was observed in the study:

In ovarian cancer, two patients had a confirmed partial response (PR) by RECIST 1.1 criteria. Both patients were treated at weekly maintenance doses of 20 mg/kg and were heavily pre-treated, having failed at least six previous treatment regimens. One of these patients had a durable PR of more than six months.
"I am particularly encouraged by the single-agent activity of 5F9 in patients with advanced, relapsed ovarian cancer, especially for women with platinum-resistant tumors who are less responsive to other therapies," said Amita Patnaik, M.D., FRCPC, Co-Director of Clinical Research at South Texas Accelerated Research Therapeutics and an investigator for this study. "These early clinical responses for 5F9 as a single agent, coupled with strong preclinical data, support Forty Seven’s combination strategy in ovarian cancer, including the recently initiated Phase 1b trial combining 5F9 with the anti-PD-L1 inhibitor, avelumab, under the Company’s existing collaboration with Merck KGaA."

About 5F9:

5F9 is a monoclonal antibody against CD47 that is designed to interfere with recognition of CD47 by the SIRPα receptor on macrophages, thus blocking the "don’t eat me" signal used by cancer cells to avoid being ingested by macrophages. Forty Seven, Inc. is initially developing 5F9, an investigational medicine, for the treatment of patients with solid tumors, acute myeloid leukemia, non-Hodgkin’s lymphoma and colorectal cancer. 5F9 has been granted Fast Track designation by the U.S. Food and Drug Administration for the treatment of relapsed or refractory diffuse large B-cell lymphoma and follicular lymphoma, two forms of B-cell non-Hodgkin’s lymphoma.

On June 3, 2018 FibroGen, Inc. (NASDAQ: FGEN), a biopharmaceutical company, reported Phase 1/2 clinical trial results of pamrevlumab in combination with standard-of-care chemotherapy in patients with locally advanced unresectable pancreatic cancer (LAPC) (Press release, FibroGen, JUN 3, 2018, View Source [SID1234527124]). . Principal investigator Vincent J. Picozzi, Jr., M.D., Director, Pancreas Center of Excellence, Virginia Mason Cancer & Digestive Diseases Institutes, presented the results in a discussion poster session at the 2018 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting in Chicago. Pamrevlumab is a proprietary first-in-class antibody targeting connective tissue growth factor (CTGF) under development for the treatment of fibrosis and fibroproliferative disorders.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

"These are some of the most exciting clinical trial results in locally advanced pancreatic cancer I have seen since I began treating pancreatic cancer patients," said Dr. Picozzi. "The data suggest that pamrevlumab in combination with chemotherapy has the potential to become a neoadjuvant treatment regimen for locally advanced unresectable pancreatic cancer patients that has not existed before."

Patients with locally advanced pancreatic cancer (without metastasis) tend to have a poor prognosis with a median survival of 9–18 months. In patients who have undergone resection of their tumor, median survival and five-year survival rates have been reported to be higher than those without resection. Therefore, treatment to achieve a surgical resection in this patient population is a meaningful treatment goal to potentially achieve a favorable overall survival outcome.

In this open-label, randomized Phase 1/2 study, pamrevlumab was administered in combination with standard-of-care chemotherapy (gemcitabine and nab-paclitaxel) and compared to treatment with chemotherapy alone in patients with locally advanced pancreatic ductal adenocarcinoma, who were not eligible for surgical resection based on histology, computerized tomography (CT) scans, and laparoscopy criteria, prior to randomization. Upon completion of the six months of study drug treatment, patients underwent surgical eligibility assessment based on pre-specified objective criteria. The study enrolled 37 patients: 24 received pamrevlumab + chemotherapy: 13 received chemotherapy alone.

At ASCO (Free ASCO Whitepaper) 2018, FibroGen reported that a higher proportion of patients whose tumor was previously considered unresectable became eligible for resection (based on protocol pre-specified post-treatment surgical eligibility criteria) after receiving pamrevlumab and chemotherapy than after receiving chemotherapy alone (at the end of 6 months of treatment), 70.8% vs. 15.4%. For those patients who met these surgical resection eligibility criteria at post-treatment assessment, individual patient condition and circumstance contributed to whether resection subsequently occurred. A higher proportion of pamrevlumab-treated patients achieved surgical resection than those received chemotherapy alone, 33.3% vs. 7.7%.

In the study, patients were followed for survival after evaluation for eligibility for resection and, when applicable, after resection. Patients who had successful resections in this study had a statistically significant longer median survival benefit as compared to patients who did not undergo resection, 40 months vs.18.6 months (p=0.0141), as of May, 2018. FibroGen is continuing to monitor study patients for survival.

"Patients with unresectable locally advanced pancreatic cancer are in need of an innovative and effective treatment with the potential to transform non-operable cancer into resectable disease," said Elias Kouchakji, M.D., Senior Vice President, Clinical Development and Drug Safety. "The updated clinical results we are reporting at ASCO (Free ASCO Whitepaper) suggest that pamrevlumab may improve the treatment outcomes for patients who are currently deemed unresectable."

About Locally Advanced Pancreatic Cancer

In locally advanced pancreatic cancer (LAPC), tumors typically encase structures, particularly blood vessels that are closely associated with the pancreas such as the superior mesenteric artery and superior mesenteric vein. Involvement of the cancer around these blood vessels precludes surgical removal of the tumor. Approximately 80% of newly diagnosed LAPC patients are classified as having unresectable disease, and patients with unresectable LAPC have a median survival only slightly better than that of patients with metastatic pancreatic cancer. Patients with resectable cancer whose tumors are surgically removed have a much better prognosis, with median survival of approximately 23 months, and some patients being cured.

About Pamrevlumab

Pamrevlumab is a first-in-class antibody developed by FibroGen to inhibit the activity of connective tissue growth factor (CTGF), a common factor in fibrotic and proliferative disorders characterized by persistent and excessive scarring that can lead to organ dysfunction and failure. Pamrevlumab is advancing towards Phase 3 clinical development for the treatment of idiopathic pulmonary fibrosis (IPF) and pancreatic cancer, and has been granted Orphan Drug Designation (ODD) in each of these indications, and is currently in a Phase 2 trial for Duchenne muscular dystrophy (DMD). Pamrevlumab recently received Fast Track designation from the U.S. Food and Drug Administration for the treatment of patients with locally advanced unresectable pancreatic cancer. Pamrevlumab has demonstrated a good safety and tolerability profile in multiple Phase 2 trials conducted to date. For information about pamrevlumab studies currently recruiting patients, please visit www.clinicaltrials.gov.

On June 3, 2018 Clovis Oncology, Inc. (NASDAQ:CLVS) and Immunomedics, Inc., (NASDAQ:IMMU) reported their intent to enter into a clinical collaboration to investigate the combination of Clovis’ Rubraca (rucaparib), a poly (ADP ribose) polymerase inhibitor (PARPi), and Immunomedics’ lead antibody-drug conjugate (ADC) product candidate, sacituzumab govitecan, as a treatment of patients with metastatic triple-negative breast cancer (mTNBC) and metastatic urothelial cancer (mUC) (Press release, Clovis Oncology, JUN 3, 2018, View Source [SID1234527115]). The planned phase 1/2 study will include an initial safety cohort followed by expansion cohorts in each of mTNBC and mUC.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

"We look forward to entering this important co-development partnership with Clovis, one of the leading innovative biotech companies, to fully leverage the scientific expertise of both companies and expand the potential for two very active agents," said Usama Malik, Chief Business Officer of Immunomedics. "There is synergy between PARPi and sacituzumab govitecan in preclinical models regardless of BRCA mutation status. This partnership will hopefully provide clinical validation for this exciting concept and bring new treatment options to disease settings with high unmet medical need."

"We are very pleased to partner with Immunomedics and are very enthusiastic about the potential synergy between rucaparib and sacituzumab govitecan," said Patrick J. Mahaffy, President and Chief Executive Officer of Clovis Oncology. "Our plan to initiate new combination studies with Immunomedics further expands our clinical development efforts in both advanced breast and bladder cancers, where there is tremendous need for new treatment options."

In preclinical studies, the combination of sacituzumab govitecan and rucaparib in TNBC cell lines in vitro resulted in synergistic growth inhibition regardless of BRCA1/2 status. In addition, the combination of sacituzumab govitecan and a PARPi also demonstrated significant antitumor effects above that observed with monotherapy in BRCA wild-type and mutant animal models of TNBC.1

"There is an opportunity to develop new treatment options for patients in the mTNBC and mUC space through our planned collaboration with Clovis Oncology, as well as potentially pursuing other indications in the future," stated Dr. Robert Iannone, Head of Research & Development and Chief Medical Officer of Immunomedics. "We are excited by the prospect that our unique ADC in combination with rucaparib could help fill a gap in treatment for cancer patients who have few available options."

Reference

Cardillo TM, Sharkey RM, Rossi DL, et al. Synthetic lethality exploitation by an anti-Trop-2-SN-38 antibody-drug conjugate, IMMU-132, plus PARP inhibitors in BRCA1/2-wild-type triple-negative breast cancer. Clin Cancer Res. 2017 Jul 1;23(13):3405-3415.
About Sacituzumab Govitecan

Sacituzumab govitecan, Immunomedics’ most advanced product candidate, is a novel, first-in-class antibody-drug conjugate (ADC). It is currently under review by the U.S. Food and Drug Administration for accelerated approval as a treatment of patients with triple-negative breast cancer who previously received at least two prior therapies for metastatic disease. If approved, sacituzumab govitecan would be the first and only ADC approved for the treatment of metastatic triple negative breast cancer.

About Rubraca

Rubraca is an oral, small molecule inhibitor of PARP1, PARP2 and PARP3 being developed in multiple tumor types, including ovarian, metastatic castration-resistant prostate, and bladder cancers, as monotherapy, and in combination with other anti-cancer agents. Exploratory studies in other tumor types are also underway. Clovis holds worldwide rights for Rubraca. Rubraca is an unlicensed medical product outside of the U.S. and EU.

Rubraca U.S. FDA Approved Indications and Important Safety Information
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 mutation (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, 5 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 for cytogenetics. 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 rucaparib can increase the systemic exposure of CYP1A2, CYP3A, CYP2C9, or CYP2C19 substrates, which may increase the risk of toxicities of these drugs. Adjust dosage of CYP1A2, CYP3A, CYP2C9, or CYP2C19 substrates, if clinically indicated. If co-administration with warfarin (a CYP2C9 substrate) cannot be avoided, consider increasing frequency of international normalized ratio (INR) monitoring.

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.

Click here for full Prescribing Information and additional Important Safety Information.