On January 4, 2024 Rigel Pharmaceuticals, Inc. (Nasdaq: RIGL) reported a collaboration with CONNECT, an international collaborative network of pediatric cancer centers, to conduct a Phase 2 clinical trial to evaluate REZLIDHIA (olutasidenib) in combination with temozolomide as maintenance therapy in newly diagnosed pediatric and young adult patients with high-grade glioma (HGG) harboring an isocitrate dehydrogenase-1 (IDH1) mutation (Press release, Rigel, JAN 4, 2024, View Source [SID1234638982]).

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!

Under the collaboration, CONNECT will include olutasidenib in CONNECT’s TarGeT-D, a molecularly guided Phase 2 umbrella clinical trial for HGG. The Rigel-sponsored arm will study post-radiotherapy administration of olutasidenib in combination with temozolomide followed by olutasidenib monotherapy as maintenance treatment in newly diagnosed pediatric and young adult patients (less than 39 years old) with IDH1 mutation positive HGG, including diffuse intrinsic pontine glioma (DIPG), an aggressive brain tumor with limited treatment options. Rigel will provide funding up to $3 million and study material over the four-year collaboration.

"We are excited to collaborate with CONNECT to evaluate olutasidenib in high grade glioma," said Raul Rodriguez, Rigel’s president and CEO. "We believe olutasidenib has potential in a variety of cancers where mIDH1 plays an important role and we look forward to generating new data in this disease state, which has a high unmet need. This collaboration builds on our hematology-oncology pipeline expansion strategy and enables us to explore the potential of olutasidenib in a focused and efficient manner."

This open label Phase 2 trial will be overseen by Drs. Santosh Valvi and Nicholas Gottardo, Perth Children’s Hospital, Dr. Michael J Fisher, Children’s Hospital of Philadelphia, and Dr. Maryam Fouladi, Nationwide Children’s Hospital, and aims to enroll approximately 60 patients. The primary objective of the olutasidenib arm of the trial is to estimate progression-free survival. The study will also characterize the safety, tolerability, and pharmacokinetics of olutasidenib in pediatric and young adult patients. The study is estimated to begin enrolling patients in the first half of 2024 and will fulfill Rigel’s post-marketing pediatric study requirement related to the FDA approval of REZLIDHIA in relapsed or refractory (R/R) AML.

In January 2023, data was published in the peer-reviewed journal Neuro-Oncology from a multicenter, open label, Phase 1b/2 trial of 26 patients with R/R and predominantly enhancing gliomas harboring an IDH1 mutation. The data showed that olutasidenib 150 mg BID was well tolerated and demonstrated preliminary evidence of clinical activity and prolonged disease control in this heavily pretreated population. The authors noted that olutasidenib is a potent, brain-penetrant, selective inhibitor of mutant IDH1.1 The paper, titled "Olutasidenib (FT-2102) in patients with relapsed or refractory IDH1-mutant glioma: A multicenter, open-label, phase Ib/II trial" can be accessed here.

REZLIDHIA is FDA-approved for the treatment of adult patients with R/R acute myeloid leukemia (AML) with a susceptible IDH1 mutation as detected by an FDA-approved test.

About REZLIDHIA
INDICATION
REZLIDHIA is indicated for the treatment of adult patients with relapsed or refractory acute myeloid leukemia (AML) with a susceptible isocitrate dehydrogenase-1 (IDH1) mutation as detected by an FDA-approved test.

WARNINGS AND PRECAUTIONS
Differentiation Syndrome
REZLIDHIA can cause differentiation syndrome. In the clinical trial of REZLIDHIA in patients with relapsed or refractory AML, differentiation syndrome occurred in 16% of patients, with grade 3 or 4 differentiation syndrome occurring in 8% of patients treated, and fatalities in 1% of patients. Differentiation syndrome is associated with rapid proliferation and differentiation of myeloid cells and may be life-threatening or fatal. Symptoms of differentiation syndrome in patients treated with REZLIDHIA included leukocytosis, dyspnea, pulmonary infiltrates/pleuropericardial effusion, kidney injury, fever, edema, pyrexia, and weight gain. Of the 25 patients who experienced differentiation syndrome, 19 (76%) recovered after treatment or after dose interruption of REZLIDHIA. Differentiation syndrome occurred as early as 1 day and up to 18 months after REZLIDHIA initiation and has been observed with or without concomitant leukocytosis.

If differentiation syndrome is suspected, temporarily withhold REZLIDHIA and initiate systemic corticosteroids (e.g., dexamethasone 10 mg IV every 12 hours) for a minimum of 3 days and until resolution of signs and symptoms. If concomitant leukocytosis is observed, initiate treatment with hydroxyurea, as clinically indicated. Taper corticosteroids and hydroxyurea after resolution of symptoms. Differentiation syndrome may recur with premature discontinuation of corticosteroids and/or hydroxyurea treatment. Institute supportive measures and hemodynamic monitoring until improvement; withhold dose of REZLIDHIA and consider dose reduction based on recurrence.

Hepatotoxicity
REZLIDHIA can cause hepatotoxicity, presenting as increased alanine aminotransferase (ALT), increased aspartate aminotransferase (AST), increased blood alkaline phosphatase, and/or elevated bilirubin. Of 153 patients with relapsed or refractory AML who received REZLIDHIA, hepatotoxicity occurred in 23% of patients; 13% experienced grade 3 or 4 hepatotoxicity. One patient treated with REZLIDHIA in combination with azacitidine in the clinical trial, a combination for which REZLIDHIA is not indicated, died from complications of drug-induced liver injury. The median time to onset of hepatotoxicity in patients with relapsed or refractory AML treated with REZLIDHIA was 1.2 months (range: 1 day to 17.5 months) after REZLIDHIA initiation, and the median time to resolution was 12 days (range: 1 day to 17 months). The most common hepatotoxicities were elevations of ALT, AST, blood alkaline phosphatase, and blood bilirubin.

Monitor patients frequently for clinical symptoms of hepatic dysfunction such as fatigue, anorexia, right upper abdominal discomfort, dark urine, or jaundice. Obtain baseline liver function tests prior to initiation of REZLIDHIA, at least once weekly for the first two months, once every other week for the third month, once in the fourth month, and once every other month for the duration of therapy. If hepatic dysfunction occurs, withhold, reduce, or permanently discontinue REZLIDHIA based on recurrence/severity.

ADVERSE REACTIONS
The most common (≥20%) adverse reactions, including laboratory abnormalities, were aspartate aminotransferase increased, alanine aminotransferase increased, potassium decreased, sodium decreased, alkaline phosphatase increased, nausea, creatinine increased, fatigue/malaise, arthralgia, constipation, lymphocytes increased, bilirubin increased, leukocytosis, uric acid increased, dyspnea, pyrexia, rash, lipase increased, mucositis, diarrhea and transaminitis.

DRUG INTERACTIONS

Avoid concomitant use of REZLIDHIA with strong or moderate CYP3A inducers.
Avoid concomitant use of REZLIDHIA with sensitive CYP3A substrates unless otherwise instructed in the substrates prescribing information. If concomitant use is unavoidable, monitor patients for loss of therapeutic effect of these drugs.
LACTATION
Advise women not to breastfeed during treatment with REZLIDHIA and for 2 weeks after the last dose.

GERIATRIC USE
No overall differences in effectiveness were observed between patients 65 years and older and younger patients. Compared to patients younger than 65 years of age, an increase in incidence of hepatotoxicity and hypertension was observed in patients ≥65 years of age.

HEPATIC IMPAIRMENT
In patients with mild or moderate hepatic impairment, closely monitor for increased probability of differentiation syndrome.

Click here for Full Prescribing Information, including Boxed WARNING.

To report side effects of prescription drugs to the FDA, visit www.fda.gov/medwatch or call 1-800-FDA-1088 (800-332-1088).

REZLIDHIA is a registered trademark of Rigel Pharmaceuticals, Inc.

On January 4, 2024 Revolution Medicines, Inc. (Nasdaq: RVMD), a clinical-stage oncology company developing targeted therapies for RAS-addicted cancers, reported that Mark A. Goldsmith, M.D., Ph.D., the company’s chief executive officer and chairman, will deliver a corporate presentation as part of the 42nd Annual J.P. Morgan Healthcare Conference on Tuesday, January 9, 2024, at 11:15 a.m. PT (Press release, Revolution Medicines, JAN 4, 2024, View Source [SID1234638981]).

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!

To access the live webcast of the presentation, please visit the "Events & Presentations" page of Revolution Medicines’ website at View Source Additionally, a replay of the webcast will be available on the "Events & Presentations" page of the Revolution Medicines website for at least 14 days following the conference.

On January 4, 2024 Portage Biotech Inc. (NASDAQ: PRTG), a clinical-stage immuno-oncology company advancing novel multi-targeted therapies for use as monotherapy and in combination, reported the outcome from the company’s comprehensive review of its pipeline in the context of the current capital raising market conditions (Press release, Portage Biotech, JAN 4, 2024, View Source [SID1234638980]).

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!

The ADPORT-201 adaptive Phase 1a/1b clinical trial of PORT-6 (adenosine 2A inhibitor) and PORT-7 (adenosine 2B inhibitor) has been progressing well with strong interest from our eight academic centers in the US. The phase 1a dose escalation portion of the trial is enrolling quickly and there have been no safety signals of concern at the doses evaluated to date. The company looks forward to presenting data from this portion of the trial at a conference later this year. We are also excited about future development with these candidates including combining our potential best-in-class adenosine 2A and adenosine 2B inhibitors at the optimum biologic doses in a biomarker enriched population and collaborating with Merck to study combinations with KEYTRUDA (pembrolizumab), Merck’s anti-PD-1 therapy.

After a review of Portage’s funding requirements, the Board of Directors has made the difficult decision to pause further drug development in the PORT-2 iNKT program. "This was a difficult decision considering the promising phase 1 safety and translational data from the non-small cell lung and melanoma trial," said Dr Ian B. Walters, chairman and CEO, "As a result, the company will evaluate a range of potential strategic options which may include among other things, finding a partner for our iNKT program or other corporate transactions." Portage does not intend to disclose developments with respect to this evaluation unless and until it determines that further disclosure is appropriate or necessary.

In connection with these developments and to extend its cash runway, Portage is implementing a cost-savings plan that includes a reduction in internal and contracted workforce, with remaining employees focusing primarily on pursuing the adenosine clinical programs.

"I want to express my sincere gratitude to our investigators and collaborators for their drug development efforts on our iNKT program, as well as the patients who participated in the trials. There is still much to learn about how to develop therapeutics for this target," remarked Dr. Walters.

KEYTRUDA is a registered trademark of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.

On January 4, 2024 OnKure, Inc. reported that the U.S. Food and Drug Administration (FDA) has cleared the Investigational New Drug (IND) application of OKI-219, a potential best-in-class, mutant selective PI3Ka H1047R inhibitor, for clinical evaluation (Press release, OnKure, JAN 4, 2024, View Source [SID1234638979]). H1047R is the most common mutation in PI3Ka, being found in 15% of breast cancer and 4% of cancers overall.

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!

There is a significant need for improved therapies targeting PI3Kα with safer and more effective drugs. OKI-219 is a highly selective inhibitor of PI3Ka H1047R, with over 100-fold selectivity for the wild-type enzyme, potentially sparing on-target toxicities that arise from inhibition of the wild-type form of the protein in normal tissues. OKI-219 shows strong, single-agent activity, including regressions at low doses in multiple PI3Ka H1047R xenograft models that are heterozygous for PI3Ka H1047R, the most common profile seen clinically for this mutation, and supporting the potential activity of highly mutant-selective inhibitors. Notably, in preclinical models, OKI-219 shows no evidence of toxicities related to PI3Ka wild-type inhibition as measured by markers of hyperglycemia, even at doses that are >15x higher than minimally active doses for antitumor activity.

Mutational activation of PI3Kα is associated with lower activity of both estrogen receptor (ER)-targeted and HER2-targeted agents in breast cancer. OKI-219 shows synergistic activity in combination with selective estrogen receptor degraders (SERDs), overcoming SERD resistance and driving strong regressions. Similarly, the combination of OKI-219 + tucatinib drives strong regressions in models of HER2+/ PI3Ka H1047R breast cancer that are resistant to HER2- inhibitors.

OnKure plans to initiate a first-in-human clinical trial, OKI-219-101 (PIKture-01), in the first quarter of 2024 that will include a dose escalation in patients with advanced solid tumors harboring the PI3Ka H1047R mutation. Subsequent evaluation of OKI-219 in combination with the SERD fulvestrant in ER+/ PI3Ka H1047R advanced breast cancer, and with the HER2-monoclonal antibody trastuzumab in HER2+/ PI3Ka H1047R advanced breast cancers will follow.

About PI3Ka and OKI-219

PI3Ka is the most frequently mutated oncogene in cancers, and PI3Ka H1047R is the most common mutation in this gene, being found in 15% of breast cancer and 4% of cancers overall. While novel drugs targeting PI3Ka have been approved, the lack of mutant selectivity of these therapeutics drives considerable on-target toxicity by inhibiting the normal version of this protein in various tissues. To address this challenge, OnKure is discovering and developing a platform of highly mutant-selective PI3Ka inhibitors with the goal of improving efficacy and safety with molecules that fully inhibit the mutant oncogene while sparing the wild-type enzyme in normal tissues. OKI-219 is a potential best-in-class, orally bioavailable, highly selective inhibitor of PI3Ka H1047R with over 100-fold selectivity for the mutated form of the enzyme compared to wild-type. OnKure believes that the wild-type sparing properties of OKI-219 should significantly improve the activity and safety relative to currently approved agents. OKI-219 is currently in Phase 1 of clinical development in solid tumor patients with PI3Ka H1047R mutations.

On January 4, 2024 Oncolytics Biotech Inc. (NASDAQ: ONCY) (TSX: ONC), a clinical-stage immunotherapeutics company focused on oncology, reported on significant 2023 accomplishments and reported corporate priorities and anticipated clinical development milestones for 2024 (Press release, Oncolytics Biotech, JAN 4, 2024, View Source [SID1234638978]).

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!

Overview: "2023 was an outstanding year for Oncolytics and the development of pelareorep as a potential cancer therapy. To date, we have studied pelareorep in more than 1,100 patients, and it has been shown to be well-tolerated with mild side effects. Promising clinical and translational results from our Phase 2 programs and mechanism of action learnings from a wide range of tumor types, as detailed below, provided consistent data and efficacy signals with durable responses that support the use of pelareorep as an immunotherapeutic agent, either as a monotherapy or in combination with other agents. These data readouts from multiple clinical studies at numerous sites and from diverse cancer indications that are clinically important make a compelling argument for pelareorep as a true backbone immunotherapy with the potential to help countless patients across a range of tumors," said Dr. Matt Coffey, President and Chief Executive Officer of Oncolytics. "We believe our cash balance and strong data, supported by our active business development program, position us well for 2024."

Positive Clinical and Translational Data: "Positive, early results from the Phase 1/2 GOBLET study in three gastrointestinal cancers – pancreatic, anal, and colorectal – showed that the combination of pelareorep and atezolizumab produced clinically meaningful improvements in response rates and survival timelines that are notably improved compared to historical results with no toxicity concerns. Translational data from studies in solid tumors, breast, pancreatic, and colorectal cancers showed that treatment with pelareorep remodels the tumor microenvironment and stimulates tumor-directed immune responses, affirming its mechanism of action as an immunotherapeutic agent. Together, these data provide a strong foundation to support advancing pelareorep into registrational-track studies, starting in 2024," continued Dr Coffey.

2024 Outlook: Dr. Coffey concluded by saying, "Looking ahead to 2024, we expect to initiate the first Phase 3 study for pelareorep in pancreatic cancer. The transition to a late-stage biopharmaceutical company will mark an important inflection point for investors, clinical collaborators and potential partners by providing a line of sight towards the path to regulatory approval and achieving our mission of developing pelareorep as an immunotherapeutic agent for cancer. We are excited to launch a new Phase 1/2 pancreatic cancer study investigating, for the first time, pelareorep in combination with modified FOLFIRINOX (mFOLFIRINOX). Finally, our discussions with regulators on a pivotal Phase 3 trial have been productive to date, and we expect to provide guidance on the registration path for metastatic breast cancer in the first half of 2024. We look forward to updating our stakeholders on our progress as the year unfolds."

Immunotherapeutic Mechanism of Action: Thomas Heineman, M.D., Ph.D., Chief Medical Officer at Oncolytics, said, "Translational data from multiple studies in 2023 have helped define pelareorep’s role in shaping the tumor microenvironment and have provided a better understanding of its ability to induce the expansion of T cell populations. Notably, the positive association between tumor response and TIL clone expansion could become a useful marker of clinical outcomes in future studies and during patient care. Moreover, these findings further distinguish pelareorep’s mechanism of action from that of other immunotherapeutic agents and provide support for its immunologic effects, which are largely driven by the introduction of its double-stranded RNA genome into cancer cells."

Financial Strength and Partnering Outlook: Kirk Look, Oncolytics’ Chief Financial Officer, commented, "Our $40 million cash balance as of September 30, 2023, and the grant funding from The Pancreatic Cancer Action Network (PanCAN) provides us with over 12 months of runway to support our operations, including the initiation of our first Phase 3 study and the BRACELET-1 survival data. We continue to have active conversations with potential partners and work diligently with clinical collaborators, including Roche and Pfizer. We believe the positive, extended dataset, including continued and durable responses, survival results, and translational observations, will provide potential partners with a well-defined and unique target product profile that will add to our discussions."

Anticipated Milestones are expected to include:

•H1 2024: Guidance on the registration path for HR+/HER2- mBC (metastatic breast cancer)
•H1 2024: Initiation of the PanCAN-supported Phase 2 Pancreatic Ductal Adenocarcinoma (PDAC) trial incorporating mFOLFIRINOX +/- atezolizumab and pelareorep
•Mid-2024: Initiation of the adaptive Phase 3 trial for pelareorep in PDAC
•Overall survival results from the BRACELET-1 study
•Expand enrollment following achievement of success criteria from the GOBLET Phase 1/2 study anal cancer cohort

Highlights of Oncolytics Biotech’s 2023 Achievements:

HR+/HER2- Metastatic Breast Cancer Program and the BRACELET-1 study
•Promising Randomized Phase 2 Data Readout Supports Previous Near Doubling of Median Overall Survival: Data presented at the 2023 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting showed that pelareorep in combination with paclitaxel (cohort 2) resulted in a near tripling of confirmed overall response rate, a 50% increase in median progression-free survival, and a hazard ratio of 0.29 (link to the PR) compared to paclitaxel monotherapy (cohort 1).

Overall survival (OS) data continues to mature since multiple patients continue to be followed for survival in the pelareorep + paclitaxel cohort. Positive results would provide Oncolytics with two successful randomized Phase 2 studies showing a meaningful OS benefit for pelareorep. The data reported so far supports the initiation of a pivotal study in mBC and makes the case for an overall survival and progression-free survival dual endpoint in a registrational trial, which could substantially reduce the time to potential approval.

Gastrointestinal Cancers and the GOBLET study cohorts
•Pancreatic Cancer Survival Data Reported at ESMO (Free ESMO Whitepaper) Supports Decision to Move to Phase 3: Updated data presented at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress 2023 showed a 62% objective response rate, nearly triple what has been seen in historical control trials. In addition, interim survival data, including median progression-free survival and median overall survival timelines, exceed historical control trials by 25% or more (link to the PR, link to the poster). Patients in this single-arm, open-label study with advanced PDAC were treated with pelareorep, atezolizumab, gemcitabine, and nab-paclitaxel.

We continue to follow the survival of several patients in this cohort as well as patients from the GOBLET study with third-line colorectal cancer, which also met the pre-defined success criteria (link to the PR, link to the poster). Having received Fast Track designation from the FDA for the treatment regimen of pelareorep, atezolizumab, gemcitabine, and nab-paclitaxel in metastatic PDAC patients last year, we were very pleased to report additional promising data for this combination, paving the way to initiate our adaptive Phase 3 trial which will now be conducted by Oncolytics, building on the positive feedback from our work with PanCAN.

Also, thanks to a US$5 million grant from PanCAN, we will examine the potential of pelareorep in combination with mFOLFIRINOX +/- atezolizumab. With these data plus the results from the adaptive Phase 3 PDAC study (pelareorep + gemcitabine + nab-paclitaxel + atezolizumab), we hope to show efficacy data for pelareorep in combination with the two most commonly used treatment regimens for pancreatic cancer patients, which could help pave the way for future broad adoption by physicians and impact a substantial number of patients.

•Anal Cancer Data – Positive Early Results in an Underserved Patient Population: Data presented at the 2nd International Multidisciplinary Anal Cancer Conference (IMACC 2023) achieved the pre-defined Simon-two-step success criteria and showed a near tripling of objective response rates compared to historical control trials in addition to a complete response (link to the PR, link to the poster). Patients in this single-arm, open-label study with second-line, unresectable squamous cell carcinoma of the anal canal (SCCA) were treated with pelareorep and atezolizumab, marking an exciting signal of efficacy in an indication where checkpoint inhibitors have had limited impact historically, and there are few treatment options.

Having met the success criteria for efficacy for this cohort, we will work closely with AIO-Studien-gGmbH (AIO), which is managing the GOBLET study, to expand the number of patients who can be treated and, hopefully, accelerate the enrollment process. With continued positive data, this could become another high-priority indication for the company.

Other Opportunities: Preclinical data published in Science Translational Medicine (link to the PR) from studies in murine tumor models showed that combining CAR T cells with pelareorep improved CAR T cell persistence and efficacy in solid tumors. An intravenous boost of pelareorep enhanced this effect and led to tumor cures in >80% of cases. We believe there is a significant opportunity here as CAR T cell therapy is currently only effective in hematological cancers, and solid tumors are the vast majority of cancers diagnosed each year. While we do not have an active program underway, we continue to have discussions on the best way to advance this effort.

I would like to take this moment to wish everyone a Happy New Year and thank our shareholders for their support. We look forward to providing additional positive updates in 2024.