On February 8, 2016 CTI BioPharma Corp. (CTI BioPharma) (NASDAQ and MTA:CTIC) reported that the Company received written communication from the U.S. Food and Drug Administration (FDA) on February 4, 2016, that the FDA has placed a partial clinical hold on the clinical studies being conducted under the Company’s Investigational New Drug ("IND") application for pacritinib (Press release, CTI BioPharma, FEB 8, 2016, View Source [SID:1234508996]) . Schedule your 30 min Free 1stOncology Demo! This clinical hold impacts part of the clinical work currently being conducted under the IND and will also affect planned clinical trials.
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Under the partial clinical hold, clinical investigators may not enroll new patients or start pacritinib as initial or crossover treatment, and patients not deriving benefit after 30 weeks of pacritinib treatment should stop using pacritinib. In addition, the FDA has recommended that the Company make certain modifications of protocols, including modifying all protocols for randomized trials to disallow crossover to pacritinib, provide certain notifications, revise relevant statements in the related investigator’s brochure and informed consent documents, and take certain other actions. The Company intends to implement the FDA’s recommendations. All clinical investigators worldwide have been delivered a notice of the partial clinical hold.
The Company intends to work together with the FDA and expects to submit modifications and revisions that address the recommendations noted above. In its written notification, the FDA cited the reasons for the partial clinical hold were that there was excess mortality and other adverse events in pacritinib-treated patients compared to the control arm in the PERSIST-1 trial. The excess mortality was most evident during the non-randomized crossover period following the initial 24 weeks of randomized treatment, during which patients in the control arm could switch to pacritinib treatment. In prior correspondence, the FDA acknowledged the difficulty addressing non-significant results, and that crossover designs can confound the interpretation of safety as well as the evaluation of survival.
After submission of the required information, the FDA has indicated that it would notify the Company whether it can continue the clinical studies under the IND.
Completion of PERSIST-2 Phase 3 Trial
Additionally, CTI BioPharma announced that as of February 3, 2016, it has completed patient enrollment in the PERSIST-2 Phase 3 clinical trial of pacritinib for the treatment of patients with myelofibrosis. PERSIST-2 is evaluating pacritinib for patients with myelofibrosis whose platelet counts are less than or equal to 100,000 per microliter (≤100,000/μL). Under the FDA partial clinical hold referenced above, patients currently receiving pacritinib may continue to do so unless they are not deriving benefit after 30 weeks of pacritinib treatment, and crossover of patients from the control arm to the pacritinib arm will not be allowed.
Year: 2016
RedHill Biopharma Announces Collaboration With Germany’s Fraunhofer Institute for Oncology Drug RP101
On February 8, 2015 RedHill Biopharma Ltd. (NASDAQ:RDHL) (TASE:RDHL) ("RedHill" or the "Company"), an Israeli biopharmaceutical company primarily focused on the development and commercialization of late clinical-stage, proprietary, orally-administered, small molecule drugs for inflammatory and gastrointestinal diseases, including cancer, reported a research collaboration with Leipzig-based Fraunhofer Institute for Cell Therapy and Immunology (IZI), a research unit of the Fraunhofer Society, one of the largest and most prominent applied research organizations in the world, for the evaluation of RedHill’s Phase II-stage oncology drug candidate, RP101(Press release, RedHill Biopharma, FEB 8, 2016, View Source [SID:1234508994]). Schedule your 30 min Free 1stOncology Demo! The research collaboration tests RP101 in pre-clinical oncology models, including pancreatic cancer, in combination with standard-of-care chemotherapies to support existing Phase I and Phase II clinical data. RP101 is a proprietary, first-in-class, orally-administered, heat shock protein 27 (Hsp27) inhibitor intended to prevent the induction of resistance to chemotherapy (chemoresistance), thus maintaining sensitivity of the tumor to chemotherapy and potentially enhancing patient survival. RP101 has completed several clinical studies, including a Phase II study in pancreatic cancer and has been granted Orphan Drug Designation for the adjunct treatment of pancreatic cancer by the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA).
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As part of the collaboration, Fraunhofer IZI is conducting real-time monitoring of tumor engraftment, tumoricidal efficacy, and response to treatment with RP101 in combination with standard-of-care chemotherapies. Results from the studies are expected during the first half of 2016. The preclinical program is intended to support the existing Phase I and Phase II clinical data with RP101 and to assess the drug’s clinical development path.
In August 2014, RedHill entered into an exclusive option agreement with RESprotect GmbH, a privately-held Germany-based biotech company, under which RedHill obtained the option to acquire the worldwide exclusive rights to RP101 for all indications, other than for the pancreatic cancer indication in South Korea. RedHill announced in July 2015 that it had extended the term of the exclusive option agreement for an additional year.
About RP101:
RP101 is a nucleoside analogue found by Prof. Rudolf Fahrig at the Fraunhofer Institute for Toxicology and Experimental Medicine (ITEM) in Hannover, Germany, to inhibit development of chemoresistance in various cancer models. It is an orally-administered, patent-protected small molecule which binds to heat shock protein 27 (Hsp27) and inhibits its anti-apoptotic effects. Hsp27 is a chaperone protein which is found in abnormally high levels in cancer cells. The overexpression of Hsp27, which results in anti-apoptotic effects, has been linked to tumor resistance to cytotoxic drugs and the development of metastasis. By inhibiting Hsp27, RP101 may prevent the induction of resistance to chemotherapy (chemoresistance) and maintain sensitivity of tumors to chemotherapy, thus potentially enhancing patient survival. RP101 has been studied in several Phase I and Phase II clinical studies with a total of 249 subjects treated, including a Phase II study in pancreatic cancer. RP101 has been granted Orphan Drug Designation for the adjunct treatment of pancreatic cancer by the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA).
Phase III trial with PM1183 in ovarian cancer (CORAIL) continues on the basis of positive recommendation by IDMC
On Febraury 8, 2016 PharmaMar (MSE:PHM) reported that the Independent Data Monitoring Committee (IDMC) has notified the Company of its recommendation that the Phase III (CORAIL) trial currently under way with PM1183 in platinum-resistant ovarian cancer patients should continue without any changes (Press release, PharmaMar, FEB 8, 2016, View Source [SID:1234508992]). Schedule your 30 min Free 1stOncology Demo! The IDMC’s recommendation came after an analysis of the safety data obtained with the first 80 patients treated in the trial. This pivotal randomised Phase III trial assesses the efficacy of PM1183 compared with the standard treatment for this indication—topotecan or pegylated liposomal doxorubicin—in a total of 420 patients.
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About PM1183 (lurbinectedin)
PM1183 is an investigational drug from the class of inhibitors of the enzyme RNA polymerase II, which is crucially involved in transcription. By targeting transcription, the drug inhibits the expression of factors important for tumor progression, and impairs the DNA repair system called NER, thereby enhancing tumor cell killing. PM1183 (lurbinectedin) is currently being investigated in different tumor types, including a Phase 3 study for platinum-resistant ovarian cancer, a Phase 2 study for BRCA1/2-associated metastatic breast cancer and a Phase 1b study for small cell lung cancer.
About ovarian cancer
It is estimated that about 240,000 cases will be diagnosed worldwide and about 150,000 women will die of ovarian cancer. Among gynaecological malignancies, it is the second most common cancer and the one causing more deathsi . Most patients with ovarian cancer have late-stage disease, in which the cancer has spread, at the moment of diagnosisii. Debulking surgery to remove most of the tumor is usually followed by chemotherapy; however, about 80% of women will relapse after treatment with platinum or a taxane and they may benefit from other therapeutic alternativesiii .
Start of Phase I clinical trial of monalizumab in combination with durvalumab
On February 8, 2016 Innate Pharma SA (the "Company" – Euronext Paris: FR0010331421 – IPH) reported the start of a Phase I combination trial of the two checkpoint inhibitors monalizumab (anti-NKG2A antibody) and durvalumab (anti-PD-L1 antibody) (Press release, Innate Pharma, FEB 8, 2016, View Source [SID:1234508991]). Schedule your 30 min Free 1stOncology Demo! This trial is a multicenter, open-label, dose-escalation and cohort-expansion study to evaluate the safety, tolerability and antitumor activity of the combination in patients with selected advanced solid tumors. It will include up to 208 patients, and will be performed in the United States and in Europe.
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Pierre Dodion, Chief Medical Officer of Innate Pharma, said: "There is a strong rationale for combining immune checkpoints inhibitors. Combinations with PD-1/PD-L1 inhibitors are of particular interest given the antitumor activity already reported for these agents and we are therefore excited to simultaneously target PD-L1 and NKG2A checkpoints in this trial". He added: "All the trials of the initial monalizumab development plan are now open and we expect to see first data in 2017. Concurrently, we are working on expanding the program to further explore the potential of monalizumab".
The rationale of the combination of durvalumab and monalizumab will be presented at a scientific meeting during 2016.
This trial is part of a global co-development and commercialization agreement with AstraZeneca for monalizumab signed in April 2015. Five Phase I/II trials are now ongoing, testing monalizumab in a variety of solid and hematologic tumors, as a single-agent and in various combinations, exploring the clinical impact of monalizumab’s ability to stimulate direct tumor killing by cytotoxic NK and T cells, and different mechanisms of synergy with other immunomodulators, including T cell activators and ADCC-inducing antibodies.
Novel cancer vaccine in combination with check point blockades holds promise
On February 5, 2016 Elios Therapeutics begins enrollment of phase I/IIa melanoma trial (NCT02678741) combining approved check point inhibitors with the Elios personalized cancer vaccine (Press release, Elios Therapeutics, FEB 5, 2016, View Source [SID:SID1234515509]).
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The trial attempts to address the unmet need of metastatic melanoma patients who fail to respond to checkpoint inhibitors(CPIs) alone
The trial will underscore the natural synergies between vaccines and CPIs
The trial will use Elios’ autologous tumor lysate (TL), particle loaded (PL), dendritic cell (DC) vaccine (TLPLDC) currently in a randomized phase IIb adjuvant trial
Elios Therapeutics, LLC, has received FDA approval to proceed with a 45-patient study that will combine the company’s novel autologous vaccine technology (TLPLDC) with standard-of-care "check point inhibitors" in metastatic melanoma patients with stable or slowly progressing disease. The study will be conducted at leading clinical research sites in the U.S. and be led by Steven O’Day, MD, Professor of Medical Oncology, Director of Immuno-Oncology, Director of Clinical Research, The John Wayne Cancer Institute, Providence Saint John’s Medical Center, Santa Monica, California.
Checkpoint inhibitors such as Yervoy, Keytruda, and Opdivo are approved for use in patients with metastatic melanoma. A small subset of patients treated with such ‘checkpoint inhibitors’ will achieve a clinical complete response; however, the majority of patients will not. "While some patients may experience partial responses or stable disease, most will see their disease progress," commented Tom Wagner, PhD, the TLPLDC vaccine inventor: "Checkpoint inhibitors work on a patient’s existing T Cell population. In order for checkpoint inhibitors to be effective, the patient must have corresponding T Cells that can recognize and attack their specific disease. It is likely that patients who do not respond or partially respond to this therapy do not have any or enough specifically-corresponding T Cells to overcome their disease. The way you create those T Cells is through autologous vaccination. Our vaccine creates a specific immune response without toxicity in a production environment that does not carry the financial burden of other therapies – possibly a perfect combination."
In early clinical studies, the TLPLDC vaccine has shown effectiveness in both the adjuvant and metastatic settings. Elios is also currently enrolling a phase II(b) 120-patient adjuvant trial in stage III and IV (resected) melanoma patients (NCT#02301611). "The unique way that the TLPLDC vaccine presents antigen to the immune system with or without other therapeutic agents and the logistical ease with which the vaccine is produced makes it easily deployed in clinical settings," said George Peoples, MD, FACS, Chief Medical Officer at Elios. "We are excited about our progress in the ongoing adjuvant trial and encouraged that adding the autologous TLPLDC vaccine to existing check point inhibitor therapy will significantly improve patient outcomes in the metastatic setting."
"Immune Checkpoint Inhibitors have revolutionized the treatment of melanoma and other cancers," said Steven O’Day, MD. "Despite durable responses and prolonged survival in many patients the majority of patients do not respond to single agent checkpoint blockade. Novel combinations of checkpoint inhibitors with other immune modulators will be critical as we build on our new found success. Novel Vaccines offer a potential additive or synergistic role in combination with PD1 inhibitors with a favorable toxicity profile."
Initial readouts for (i) the 45 patient phase I/II(a) trial of the TLPLDC vaccine in combination with checkpoint inhibitors in metastatic melanoma patients, and (ii) the 120 patient phase II(b) adjuvant trial in stage III and IV (resected) patients to prevent recurrence are both expected in December 2016.