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Combination immunotherapy benefits subset of patients with advanced prostate cancer

On September 10, 2020 The University of Texas MD Anderson Cancer reported that Results from a Phase II trial led by researchers at Center suggest that a combination of ipilimumab (anti-CTLA-4) plus nivolumab (anti-PD-1) can generate durable responses in a subset of patients with metastatic castration-resistant prostate cancer (mCRPC), an "immune-cold" cancer that does not typically respond well to immunotherapy (Press release, MD Anderson, SEP 10, 2020, View Source [SID1234564946]).

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In a cohort of patients without previous chemotherapy treatment, the overall response rate (ORR) was 25% and median overall survival (OS) was 19 months. In a post-chemotherapy cohort, the ORR was 10% and media OS was 15.2 months. Four patients (two in each cohort) achieved a complete response.

The results of the CheckMate 650 trial, published today in Cancer Cell, are the first report of combination immune checkpoint inhibitors in mCRPC. Early results from this study were presented at the 2019 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Genitourinary Cancers Symposium. Based on the findings, alternate dosing regimens are now being evaluated in an expanded clinical trial to reduce treatment-related toxicities.

"Historically, prostate cancer has been very resistant to checkpoint inhibitors because it is immunologically cold with few tumor-infiltrating T cells," said principal investigator Padmanee Sharma, M.D., Ph.D., professor of Genitourinary Medical Oncology and Immunology. "These results suggest that a combination approach to increase T cell infiltration and then block inhibitory pathways may be a useful strategy for treating these patients. Going forward, we plan to optimize the schedule and dosing to improve the safety profile."

Designing a combination strategy

In previous research published in Nature Medicine, Sharma and colleagues discovered that prostate cancers deploy multiple mechanisms to dampen the anti-tumor immune response. Although anti-CTLA-4 therapy could recruit T cells, the tumor-infiltrating T cells elicited compensatory inhibitory pathways, including immune-suppressing proteins PD-L1 and VISTA.

This would explain why previous clinical trials evaluating single-agent checkpoint inhibitors have not been effective in treating patients with mCRPC, said Sharma, who co-directs MD Anderson’s immunotherapy platform, part of the institution’s Moon Shots Program.

The researchers hypothesized that combining anti-CTLA-4 (ipilimumab) with anti-PD-1 (nivolumab) may be effective in bringing T cells into the tumor and overcoming the resulting immunosuppressive response.

The multi-institution, open-label study enrolled 90 men with mCRPC, who received the combination therapy every three weeks. Patients were enrolled in two cohorts: one with and one without prior chemotherapy. Participants were 77.8% Caucasian, 10% Black/African-American and 12.2% other.

In addition to response rates, the combination therapy achieved disease control in 46.9% and 13.3% of patients, with a median progression-free survival of 5.5 and 3.8 months in the pre- and post-chemotherapy cohorts, respectively.

Despite the positive responses, grade 3 and 4 treatment-related adverse events occurred in 42.2% of pre-chemotherapy patients and 53.3% of post-chemotherapy patients. The most common of these events was diarrhea, pneumonitis, colitis and increased lipase. Treatment-related adverse events led to discontinuation of therapy in a total of 31 patients. There were four treatment-related deaths, two in each cohort.

"There were patients who had clear benefit as a result of treatment, but there also were patients who had serious adverse events, which led us to amend the protocol to evaluate alternate schedules and doses and improve the safety of this approach," said Sharma.

Based on these data, the trial has been expanded to include more than 400 patients, with different dosing and schedules to identify strategies that can improve efficacy and minimize toxicities.

Exploring biomarkers associated with response

The researcher team also conducted analyses to identify potential biomarkers associated with clinical outcomes in these patients.

While this study represents a small number of patients, their findings suggest that the combination may be more effective in patients with a relatively high tumor mutational burden (TMB). This is in agreement with previous work that suggests certain patients with mCRPC may respond to checkpoint blockade despite having low TMB relative to other cancers, such as melanoma and lung cancer.

"The current study represents the first step in trying to identify mCRPC patients who would benefit from combination therapy with ipilimumab plus nivolumab based on chemotherapy exposure as well as preliminary biomarker analyses," said co-author Sumit Subudhi, M.D., Ph.D., assistant professor of Genitourinary Medical Oncology. "The data generated to date are encouraging, but we clearly have more work to do in the expansion cohort as we try to administer effective combination strategies with fewer toxicities."

This study was supported by Bristol-Meyers Squibb and ONO Pharmaceutical Company, Limited. Sharma is a member of the Parker Institute for Cancer Immunotherapy (PICI) and co-director of PICI at MD Anderson. A full list of authors and their disclosures can be found with the paper here.

Midatech Pharma Plc (“Midatech” or the “Company”) Interim results for the six months ended 30 June 2020

On September 10, 2020 Midatech Pharma PLC (AIM: MTPH.L; Nasdaq: MTP), a drug delivery technology company focused on improving the bio-delivery and bio-distribution of medicines, reported its unaudited interim results for the six months ended 30 June 2020 (Press release, Midatech Pharma, SEP 10, 2020, View Source [SID1234564945]).

OPERATIONAL HIGHLIGHTS (including post period end)

·In March, an exploratory study was initiated with MTX110 by Columbia University in five patients with DIPG using an alternative convection enhanced delivery system.

·In March, the Company announced a wide-ranging Strategic Review, updated in April to include a Formal Sale Process under the Takeover Code. The Formal Sale Process was subsequently terminated in July.

·In March, the decision was taken to terminate further in-house development of the MTD201 programme with immediate effect although the asset remains available for licensing. All activities connected with MTD201 have been wound down expeditiously and the manufacturing facilities in Bilbao have been closed. Following the termination of in-house development of MTD201, the Company realigned its strategy towards exploiting its Q-Sphera technology more broadly.

·In April, an exploratory study was initiated with MTX110 by the University of Texas, Houston in five patients with recurrent medulloblastoma.

·In June, the Company signed a research collaboration with Dr Reddy’s Laboratories Ltd under which Midatech is deploying its in-house expertise and Q-Sphera drug delivery platform to medicines nominated by Dr Reddy’s.

·In July, the Company signed a collaboration with an unnamed European affiliate of a global pharmaceutical company, to establish the application of the Q-Sphera platform to new modalities in drug delivery.

FINANCIAL HIGHLIGHTS (including post period end)

·Total revenue in H1 2020 was £0.17m (H1 2019: £0.45m). Total revenue represents income from R&D collaborations plus grant revenue.

·Research and development costs increased by 15% to £3.99m (H1 2019: £3.46m) as a result of lower MTX110 development costs, redundancy costs of £0.88m and write-down of Spain assets of £0.55m, offset by a negative share-based payment charge of £0.35m.

·Administrative expenses increased to £2.93m (H1 2019: £2.05m) and included £0.35m one-time costs associated with Spanish Government loans, £0.07m UK redundancy costs and a £0.51m increase in legal and professional fees.

·Impairment of intangible assets of £11.59m (H1 2019: Nil) related to the termination of further in-house development of MTD201 and associated IPRD and goodwill.

·Net cash used in operating activities (after changes in working capital) in H1 2020 was £7.09m, compared with £4.56m in H1 2019.

·In May, in a concurrent Registered Direct Offering in the US and a Placing in the UK, the Company raised £4.26m before expenses through the sale of 15.76m ordinary shares at £0.27 per share and warrants exercisable for 16.55m ordinary shares at £0.34 per share.

·In July, the Company raised an additional £5.75m before expenses in an oversubscribed UK Placing, including a Broker Option, through the sale of 21.3m ordinary shares at £0.27 per share with no warrants.

·The cash balance at 30 June 2020 was £4.33m.

Immunomic Therapeutics Inc. Expands into South Korea

On September 10, 2020 Immunomic Therapeutics, Inc., ("ITI"), a privately-held clinical-stage biotechnology company pioneering the study of nucleic acid immunotherapy platforms, reported that originating in the United States recently opened its first office in South Korea (Press release, Immunomic Therapeutics, SEP 10, 2020, View Source [SID1234564944]). This continues to build on ITI’s overall strategy to be the partner-of-choice for innovative biotechnology companies in emerging centers of excellence worldwide.

ITI is bringing its strategic business model to South Korea – designed to bring together the world’s leading experts and cutting-edge science to advance research in the Glioblastoma (GBM) field and to deploy ITI-1000 to the Asian population. ITI-1000 is a cell therapy powered by ITI’s UNITE platform that is currently being evaluated in a Phase II clinical trial (ATTAC-II) in collaboration with researchers at the University of Florida and Duke University. ITI-1001 is an alternative, cell-free approach to treating GBM. The company held a pre-IND meeting earlier this year for ITI-1001 and expects to be able to file an Investigational New Drug Application (IND) with the U.S. Food and Drug Administration (FDA).

The recent $61.3M financing led by HLB Co., LTD, a global pharmaceutical company focused on developing novel cancer drugs enables ITI to expand and form partnerships with local companies and research institutions to accelerate the development and commercialization of Korean pharmaceutical discoveries for the global markets.

"South Korea is an emerging center of biopharma research innovation, and we are excited to open ITI’s new office in a location where talented Korean researchers are doing groundbreaking work," said William G. Hearl, CEO, Immunomic Therapeutics. "We look forward to collaborating with HLB Bio Group to raise Korea’s profile as a global center of biopharma innovation and make exceptional therapies available for patients."

The new ITI office in South Korea is located in Teheran-ro, Gangnam-gu, Seoul, an area well established as a high-tech business zone in the city. Many Korean biopharma and biotech companies have headquarters in this area of Seoul.

In addition to its newly opened South Korean office, ITI headquarters is located in the U.S.

Syros Pharmaceuticals to Present at Cantor Virtual Global Healthcare Conference

On September 10, 2020 Syros Pharmaceuticals (NASDAQ:SYRS), a leader in the development of medicines that control the expression of genes, reported that its Chief Executive Officer, Nancy Simonian, M.D., will present a corporate overview at the Cantor Virtual Global Healthcare Conference. Details are as follows (Press release, Syros Pharmaceuticals, SEP 10, 2020, View Source [SID1234564943]):

Cantor Virtual Global Healthcare Conference:
Date: Thursday, September 17
Time: 8:40 a.m. ET

A live webcast of the presentation will be available on the Investors & Media section of the Syros website at www.syros.com. An archived replay of the webcast will be available for approximately 30 days following the presentation.

Clovis Oncology Announces Oral Plenary Session Presentation at International Gynecologic Cancer Society (IGCS) Digital Annual Global Meeting

On September 10, 2020 Clovis Oncology, Inc. (NASDAQ: CLVS), reported that an abstract featuring data from an exploratory analysis of the ARIEL3 clinical study evaluating Rubraca (rucaparib) as maintenance treatment in recurrent ovarian cancer has been accepted for presentation in an oral plenary session at the International Gynecologic Cancer Society (IGCS) Digital Annual Global Meeting taking place September 10–13 (Press release, Clovis Oncology, SEP 10, 2020, View Source [SID1234564942]). The findings of the analysis demonstrate that rucaparib maintenance treatment can lead to a clinically meaningful delay in starting subsequent therapy and lasting clinical benefits in patients withBRCA1- or BRCA2-mutant ovarian cancer.

"This exploratory analysis examining the subgroup of patients with advanced recurrent ovarian cancer and aBRCA1 or BRCA2 mutation suggest the durability of the clinical benefit of rucaparib maintenance," said Johanne Weberpals M.D., Gynecologic Oncologist, Ottawa Hospital Research Institute. "These data reinforce the potential benefit of rucaparib in this patient population."

"Together with ARIEL3 results we have previously published and presented, these data highlight the clinical benefit that Rubraca offers as a maintenance therapy for patients with recurrent ovarian cancer," said Patrick J. Mahaffy, President and CEO of Clovis Oncology. "We look forward to sharing these data with the research and medical community at this year’s digital IGCS global meeting and continuing the important dialogue around the benefits of Rubraca for the treatment of advanced ovarian cancer."

Following are details regarding the Rubraca abstract to be presented today at IGCS:

Abstract Number: IGCS20_1268- Postprogression Efficacy Outcomes from the Phase 3 ARIEL3 Study of Rucaparib in Patients With Platinum-Sensitive Recurrent Ovarian Carcinoma Associated With Either BRCA1 or BRCA2 Mutations

Presenting Author: Johanne I. Weberpals, MD
Session: Plenary I
The presentation will take place during the Plenary I session which will be broadcast on Thursday, September 10, 2020 from 14:00-15:00 UTC; the specific presentation time is 14:47-14:54 UTC. In addition, the presentation will be available at View Source following the Plenary I session.

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 is an unlicensed medical product outside of the U.S. and Europe.

Rubraca (rucaparib) European Union (EU) authorized use and Important Safety Information

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

Rubraca is indicated as monotherapy treatment of adult patients with platinum sensitive, relapsed or progressive, BRCA mutated (germline and/or somatic), high-grade epithelial ovarian, fallopian tube, or primary peritoneal cancer, who have been treated with ≥2 prior lines of platinum-based chemotherapy, and who are unable to tolerate further platinum-based chemotherapy.

Efficacy of Rubraca as treatment for relapsed or progressive EOC, FTC, or PPC has not been investigated in patients who have received prior treatment with a PARP inhibitor. Therefore, use in this patient population is not recommended.

Summary warnings and precautions:

Hematological toxicity

During treatment with Rubraca, events of myelosuppression (anemia, neutropenia, thrombocytopenia) may be observed and are typically first observed after 8–10 weeks of treatment with Rubraca. These reactions are manageable with routine medical treatment and/or dose adjustment for more severe cases. Complete blood count testing prior to starting treatment with Rubraca, and monthly thereafter, is advised. Patients should not start Rubraca treatment until they have recovered from hematological toxicities caused by previous chemotherapy (CTCAE grade ≥1).

Supportive care and institutional guidelines should be implemented for the management of low blood counts for the treatment of anemia and neutropenia. Rubraca should be interrupted or dose reduced according to Table 1 (see Posology and Method of Administration [4.2] of the Summary of Product Characteristics [SPC]) and blood counts monitored weekly until recovery. If the levels have not recovered to CTCAE grade 1 or better after 4 weeks, the patient should be referred to a hematologist for further investigations.

MDS/AML

MDS/AML, including cases with fatal outcome, have been reported in patients who received Rubraca. The duration of therapy with Rubraca in patients who developed MDS/AML varied from less than 1 month to approximately 28 months.

If MDS/AML is suspected, the patient should be referred to a hematologist for further investigations, including bone marrow analysis and blood sampling for cytogenetics. If, following investigation for prolonged hematological toxicity, MDS/AML is confirmed, Rubraca should be discontinued.

Photosensitivity

Photosensitivity has been observed in patients treated with Rubraca. Patients should avoid spending time in direct sunlight because they may burn more easily during Rubraca treatment; when outdoors, patients should wear a hat and protective clothing, and use sunscreen and lip balm with sun protection factor of 50 or greater.

Gastrointestinal toxicities

Gastrointestinal toxicities (nausea and vomiting) are frequently reported with Rubraca, and are generally low grade (CTCAE grade 1 or 2), and may be managed with dose reduction (refer to Posology and Method of Administration [4.2], Table 1 of the SPC) or interruption. Antiemetics, such as 5-HT3 antagonists, dexamethasone, aprepitant and fosaprepitant, can be used as treatment for nausea/vomiting and may also be considered for prophylactic (i.e. preventative) use prior to starting Rubraca. It is important to proactively manage these events to avoid prolonged or more severe events of nausea/vomiting which have the potential to lead to complications such as dehydration or hospitalization.

Embryofetal toxicity

Rubraca can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings from animal studies. In an animal reproduction study, administration of Rubraca to pregnant rats during the period of organogenesis resulted in embryo-fetal toxicity at exposures below those in patients receiving the recommended human dose of 600 mg twice daily (see Preclinical Safety Data [5.3] of the SPC).

Pregnancy/contraception

Pregnant women should be informed of the potential risk to a fetus. Women of reproductive potential should be advised to use effective contraception during treatment and for 6 months following the last dose of Rubraca (see section 4.6 of the SPC). A pregnancy test before initiating treatment is recommended in women of reproductive potential.

Click here to access the current SPC. Healthcare professionals should report any suspected adverse reactions via their national reporting systems.

Rubraca U.S. FDA Approved Indications

Ovarian Cancer

Rubraca is indicated for the maintenance treatment of adult women 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 for the treatment of adult women with a 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. Select patients for therapy based on an FDA-approved companion diagnostic for Rubraca.

Prostate Cancer

Rubraca is indicated for the treatment of adult patients with a deleterious BRCA mutation (germline and/or somatic)-associated metastatic castration-resistant prostate cancer (mCRPC) who have been treated with androgen receptor-directed therapy and a taxane-based chemotherapy. This indication is approved under accelerated approval based on objective response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

Select Important Safety Information

Myelodysplastic Syndrome (MDS)/Acute Myeloid Leukemia (AML) occur in patients treated with Rubraca, and are potentially fatal adverse reactions. In 1146 treated patients, MDS/AML occurred in 20 patients (1.7%), including those in long term follow-up. Of these, 8 occurred during treatment or during the 28 day safety follow-up (0.7%). The duration of Rubraca treatment prior to the diagnosis of MDS/AML ranged from 1 month to approximately 53 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 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. For males on Rubraca treatment who have female partners of reproductive potential or who are pregnant, effective contraception should be used during treatment and for 3 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 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%).

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.