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ASTRAZENECA’S COMBINATION OF DURVALUMAB WITH TREMELIMUMAB SHOWS CLINICAL ACTIVITY IN NON-SMALL CELL LUNG CANCER IRRESPECTIVE OF PD-L1 STATUS

On February 8, 2016 AstraZeneca and MedImmune, its global biologics research and development arm, reported publication in The Lancet Oncology of a Phase Ib study (study 006), showing antitumour activity of combination treatment with durvalumab and tremelimumab, in patients with locally advanced or metastatic non-small cell lung cancer (NSCLC), irrespective of PD-L1 status (Press release, AstraZeneca, FEB 8, 2016, View Source [SID:1234508997]).1

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In a cohort of 26 patients treated with durvalumab 10-20 mg/kg plus tremelimumab 1 mg/kg, and followed for ≥24 weeks, the confirmed objective response rate (ORR) was 23% (95% confidence interval 9-44%).1 Comparable ORRs were seen in patients from this cohort with PD-L1 positive and negative tumours (22% and 29% respectively). Durvalumab was administered intravenously every four weeks (q4w) for 13 doses or every 2 weeks (q2w) for 26 doses, and tremelimumab was administered q4w for six doses followed by every 12 weeks (q12w) for three doses.

Data on all 56 patients treated with durvalumab 10-20 mg/kg q2w or q4w plus tremelimumab 1 mg/kg showed a manageable safety profile for an advanced NSCLC population. Thirty per cent of patients had ≥1 related Grade 3/4 adverse events (AE) and 16% discontinued treatment due to a related adverse event.

Dr Scott J. Antonia, Chair of the Department of Thoracic Oncology at Moffitt Cancer Center, Tampa, Florida, USA, said: "Combination therapy with durvalumab and tremelimumab demonstrated antitumour activity in patients with NSCLC regardless of PD-L1 status, including in patients with no evidence of tumour cell membrane PD-L1 staining. The results suggest that this combination has potential as a treatment option for patients with PD-L1 negative tumours whose needs are not addressed by currently available therapies, including immunotherapies."

With the recent introduction of checkpoint inhibitors, the presence of PD-L1 expression in a tumour is considered a significant biomarker for response to PD-L1 blockade.2 Less than half of patients with NSCLC have tumours that are PD-L1 positive,1 leaving a significant unmet medical need in the PD-L1 negative patient population.

Dr Ed Bradley, Senior Vice President, Oncology, MedImmune, said: "The newly published data are an important milestone in our scientific understanding of the patient population likely to achieve the greatest benefit from the combination of durvalumab and tremelimumab. The latest findings reinforce our belief that the combination strategy we are pursuing is key to the future success of immuno-oncology treatment."

Durvalumab is an investigational human monoclonal antibody directed against programmed death ligand-1 (PD-L1), which blocks the interactions between PD-L1 and both PD-1 and B7.1, reversing in some tumours the ability of tumour cells to avoid detection by the immune system.3 Tremelimumab inhibits the activity of cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) to boost the immune response against cancer cells.4 Preclinical data suggested that targeting both PD-L1 and CTLA-4 may have additive or synergistic effects.5

A preliminary analysis of data from Study 006 was presented at the annual meeting of the Society for Immunotherapy in Cancer (SITC) (Free SITC Whitepaper), in November 2015. The Lancet Oncology publication provides a more detailed analysis with a longer follow up period and more mature data set of confirmed responses, with a focus on those which informed the selection of durvalumab 20 mg/kg plus tremelimumab 1 mg/kg, every four weeks, for ongoing Phase III trials.1

Durvalumab and tremelimumab are pipeline products under development and, as such, are not approved by the US Food and Drug Administration, European Medicines Agency or any other regulatory agency for the uses under investigation. Information regarding these investigational products should under no circumstances be regarded as a recommendation for their use or of their safety or efficacy.

– ENDS –

NOTES TO EDITORS

About durvalumab (MEDI4736)

Durvalumab is an investigational human monoclonal antibody directed against programmed death ligand-1 (PD-L1). Signals from PD-L1 help tumours avoid detection by the immune system.2 Durvalumab blocks these signals, countering the tumour’s immune-evading tactics.3 Durvalumab is being investigated in an extensive clinical trial programme.

About tremelimumab

Tremelimumab is a fully human anti-CTLA-4 antibody. By blocking the activity of CTLA-4, tremelimumab "releases the brakes" on T cell activation and boosts the immune response against cancer cells.4,6 In animal models, CTLA-4 blockade by anti-CTLA-4 antibodies such as tremelimumab, has been shown to promote antitumour immune responses.4 In 2015, tremelimumab was granted Orphan Drug Designation by the US Food and Drug Administration as a potential treatment for malignant mesothelioma.

CTI BioPharma Provides Update On Investigational Agent Pacritinib

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]) .

This clinical hold impacts part of the clinical work currently being conducted under the IND and will also affect planned clinical trials.

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.

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]).

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).

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]).

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.

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]).

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.

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.