On May 27, 2022 Novartis reported the US Food and Drug Administration (FDA) has granted accelerated approval for Kymriah (tisagenlecleucel) for the treatment of adult patients with relapsed or refractory (r/r) follicular lymphoma (FL) after two or more lines of systemic therapy (Press release, Novartis, MAY 27, 2022, View Source [SID1234615211]). In accordance with the Accelerated Approval Program, continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial(s). Kymriah is now FDA approved in three indications and remains the only CAR-T cell therapy approved in both adult and pediatric settings1.

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"We are proud of today’s FDA approval of a third indication for Kymriah. We hope this treatment option that has the potential for long-lasting results may help break the unrelenting cycle of treatment for patients with follicular lymphoma," said Victor Bulto, President, Novartis Innovative Medicines US. "We are on a mission to build on our pioneering work in cell therapy and continue to innovate for patient impact."

The approval is based on data from the Phase II ELARA trial, a single-arm, open-label trial, in which 90 patients were evaluated for efficacy with a median follow-up of approximately 17 months. Eighty-six percent of patients treated with Kymriah achieved a response including 68% who experienced a complete response1.

Prolonged durable response to treatment was demonstrated with an estimated 85% of patients who achieved a complete response still in response 12 months after initial response1. Kymriah was shown to be effective in high-risk patients including those who were heavily pretreated or had refractory disease, POD24, bulky disease or those with high Follicular Lymphoma International Prognostic Index (FLIPI) scores1.

For the 97 patients evaluable for safety at 21 months of median follow-up, the safety profile of Kymriah was remarkable1. Fifty-three percent of patients experienced any-grade cytokine release syndrome (CRS), as defined by the Lee scale, and there were no reported cases of high-grade (grade 3 or higher) CRS1. Forty-three percent of patients experienced any-grade neurologic events; grade 3 or higher neurologic events were seen in only 6% of patients1. Eighteen percent of patients (17 of 97 patients) were infused in an outpatient setting3.

"Patients with follicular lymphoma who relapse or don’t respond to treatment have a poor prognosis and may face a series of treatment options without a meaningful, lasting response," said Stephen J. Schuster, MD, the Robert and Margarita Louis-Dreyfus Professor in Chronic Lymphocytic Leukemia and Lymphoma in the Division of Hematology Oncology and Director, Lymphoma Program and Translational Research at the University of Pennsylvania’s Abramson Cancer Center, institutional Principal Investigator on the trial. "This new, effective option for patients with follicular lymphoma may offer long-term benefit."

While follicular lymphoma is typically an indolent type of cancer, patients with FL may be exposed to a median of four lines of treatment, with an upper range of 13 lines4,5. Although there are multiple systemic therapies available, the efficacy of these regimens drops off rapidly in later lines6.

"The approval of Kymriah offers patients with relapsed or refractory follicular lymphoma a new treatment option and new hope for improving patient outcomes," said Meghan Gutierrez, Chief Executive Officer at the Lymphoma Research Foundation. "Having this single infusion treatment option helps to transform the way healthcare providers approach this type of blood cancer and we commend those who have contributed to the acceleration of scientific research for the benefit of patients."

In early May 2022, the European Commission approved Kymriah for the treatment of adult patients with r/r FL after two or more lines of systemic therapy, the third indication for which Kymriah is available to patients in the European Union.

Additional efficacy and safety details for Kymriah and full Prescribing Information can be found at View Source

About Novartis commitment to Oncology Cell Therapy
As part of the unique Novartis Oncology strategy to pursue four cancer treatment platforms – radioligand therapy, targeted therapy, immunotherapy and cell and gene therapy – we strive for cures through cell therapies in order to enable more patients to live cancer-free. We will continue to pioneer the science and invest in our manufacturing and supply chain process to further advance transformative innovation.

Novartis was the first pharmaceutical company to significantly invest in pioneering CAR-T research and initiate global CAR-T trials. Kymriah, the first approved CAR-T cell therapy, developed in collaboration with the Perelman School of Medicine at the University of Pennsylvania, is the foundation of the Novartis commitment to CAR-T cell therapy.

We have made strong progress in broadening our delivery of Kymriah, which is currently available for use in at least one indication in 30 countries and at more than 370 certified treatment centers, with clinical and real-world experience from administration to more than 6,900 patients. We continue to pioneer in cell therapy, leveraging our vast experience to develop next-generation CAR-T cell therapies. These therapies will utilize our new T-Charge platform being evaluated to expand across hematological malignancies and bring the hope for a cure to patients with other cancer types.

Novartis has a comprehensive, integrated global CAR-T manufacturing footprint that strengthens the flexibility, resilience and sustainability of the Novartis manufacturing and supply chain.

Important Safety Information
KYMRIAH may cause side effects that are severe or life-threatening, such as cytokine release syndrome (CRS) or neurological toxicities. Patients with CRS may experience symptoms including difficulty breathing, fever (100.4◦F/38◦C or higher), chills/shaking chills, severe nausea, vomiting and diarrhea, severe muscle or joint pain, very low blood pressure, or dizziness/lightheadedness. Patients may be admitted to the hospital for CRS and treated with other medications.

Patients with neurological toxicities may experience symptoms such as altered or decreased consciousness, headaches, delirium, confusion, agitation, anxiety, seizures, difficulty speaking and understanding, or loss of balance. Patients should be advised to call their health care provider or get emergency help right away if they experience any of these signs and symptoms of CRS or neurological toxicities.

Because of the risk of CRS and neurological toxicities, KYMRIAH is only available through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the KYMRIAH REMS.

Patients may experience hemophagocytic lymphohistiocytosis/macrophagocytic activation syndrome. Patients should discuss the possibility of developing this life-threatening condition with their health care provider.

Serious allergic reactions, including anaphylaxis, may occur after KYMRIAH infusion. KYMRIAH can increase the risk of life-threatening infections that may lead to death. Patients should be advised to tell their health care provider right away if they develop fever, chills, or any signs or symptoms of an infection.

Patients may experience prolonged low blood cell counts (cytopenias), where 1 or more types of blood cells (red blood cells, white blood cells, or platelets) are decreased. The patient’s health care provider will do blood tests to check all their blood cell counts after treatment with KYMRIAH. Patients should be advised to tell their health care provider right away if they get a fever, are feeling tired, weak, or short of breath, or have bruising or bleeding.

Patients may experience hypogammaglobulinemia, a condition in which the level of immunoglobulins (antibodies) in the blood is low and the risk of infection is increased. It is expected that patients may develop hypogammaglobulinemia with KYMRIAH and may need to receive immunoglobulin replacement for an indefinite amount of time following treatment with KYMRIAH. Patients should tell their health care provider about their treatment with KYMRIAH before receiving a live vaccine.

After treatment with KYMRIAH, patients will be monitored lifelong by their health care provider, as they may develop secondary cancers or recurrence of their cancer.

Patients should not drive, operate heavy machinery, or do other dangerous activities for 8 weeks after receiving KYMRIAH because the treatment can cause temporary memory and coordination problems, including sleepiness, confusion, weakness, dizziness, and seizures.

Some of the most common side effects of KYMRIAH are difficulty breathing, fever (100.4°F/38°C or higher), chills/shaking chills, confusion, severe nausea, vomiting and diarrhea, severe muscle or joint pain, very low blood pressure, dizziness/lightheadedness, and headache. However, these are not all the possible side effects of KYMRIAH. Patients should talk to their health care provider for medical advice about side effects.

Prior to a female patient starting treatment with KYMRIAH, their health care provider may do a pregnancy test. No information is available for KYMRIAH use in pregnant or breastfeeding women. Therefore, KYMRIAH is not recommended for women who are pregnant or breastfeeding. Patients should talk to their health care provider about birth control and pregnancy.

Patients should tell their health care provider about all the medicines they take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.

After receiving KYMRIAH, patients should be advised that some commercial HIV tests may cause a false-positive test result. Patients should also be advised not to donate blood, organs, tissues, sperm, oocytes, and other cells after receiving KYMRIAH.

On May 27, 2022 Dr. Reddy’s Laboratories Ltd. (BSE: 500124, NSE: DRREDDY, NYSE: RDY, NSEIFSC: DRREDDY, along with its subsidiaries together referred to as "Dr. Reddy’s") reported the launch of Pemetrexed for Injection, 100 mg and 500 mg Single-Dose Vials, the generic equivalent of ALIMTA (pemetrexed for injection) in the U.S. Market approved by the U.S. Food and Drug Administration (USFDA) (Press release, Dr Reddy’s, MAY 27, 2022, View Source [SID1234615210]).

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The ALIMTA brand and generic had U.S. sales of approximately $1239 million MAT for the most recent twelve months ending in March 2022 according to IQVIA Health*.

Dr. Reddy’s Pemetrexed for Injection is supplied in 100 mg and 500 mg single-dose vials.

On May 27, 2022 City of Hope, one of the largest cancer research and treatment organizations in the United States, reported it would present research on promising treatments for bladder and blood cancers, as well as studies on precision medicine and an experimental cancer vaccine, at the 2022 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper)’s (ASCO) (Free ASCO Whitepaper) annual conference from June 3 to 7 in Chicago (Press release, City of Hope, MAY 27, 2022, View Source [SID1234615209]).

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More than 40,000 oncology professionals and others will attend the conference, or join virtually, to learn about the latest scientific research on cancer treatment, detection and prevention.

"For the first time in two years, our doctors and scientists will meet in person to present the innovative cancer research that City of Hope is known for and learn from colleagues," said Steven T. Rosen, M.D., City of Hope provost and chief scientific officer and Irell & Manella Cancer Center Director’s Distinguished Chair. "City of Hope’s commitment to expand access to specialty cancer care and remove barriers for underserved patients also aligns closely with ASCO (Free ASCO Whitepaper)’s conference theme this year to advance equitable care through innovation."

City of Hope doctors and scientists will present oral and poster presentations on a wide range of topics:

Cabozantinib shows enhanced response to checkpoint inhibitor in patients with solid tumors

Findings from three groups of the COSMIC-021 study show benefit of cabozantinib plus atezolizumab in certain patients with locally advanced or metastatic urothelial carcinoma.

Cabozantinib is a tyrosine kinase inhibitor that may enhance a patient’s response to immune checkpoint inhibitors, which can help the body’s immune system fight cancer. COSMIC-021 is a multicenter Phase 1b study evaluating cabozantinib plus atezolizumab (an anti‒PD-L1 therapy) in patients with various solid tumors (NCT03170960). The findings from cohorts 3, 4 and 5 will be presented during an oral presentation at ASCO (Free ASCO Whitepaper)’s Annual Meeting on Friday, June 3, at 3:57 p.m. CDT.

The study enrolled patients with locally advanced or metastatic urothelial carcinoma, including cancer of the bladder, renal pelvis, ureter and urethra. Patients in cohorts 3 and 4 had not undergone previous therapy and were either eligible for cisplatin-based chemotherapy, cohort 4, or were not eligible for it, cohort 3. Patients in cohort 5 had been previously treated with an immune-checkpoint inhibitor, but not with a vascular endothelial growth factor receptor-tyrosine kinase inhibitor.

"Cabozantinib plus atezolizumab demonstrated encouraging clinical activity with manageable toxicity in patients with inoperable locally advanced or metastatic urothelial carcinoma," said Sumanta Kumar Pal, M.D., co-director of City of Hope’s Kidney Cancer Program and the study’s primary investigator. "The therapy has promise both as a first-line systemic therapy in patients who haven’t been treated with cisplatin-based chemotherapy and as a second-line therapy in patients who have been treated with an immune-checkpoint inhibitor."

After enrollment in the trial, the patients were followed by computed tomography and magnetic resonance imaging scans performed every six weeks for the first year and every 12 weeks thereafter. The study sought to measure the objective response rate, which is the proportion of patients with a complete or partial response, as assessed by use of Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, a standard way to measure a tumor’s response to treatment. Thirty patients were enrolled in both cohorts 3 and 4. Thirty-one patients were enrolled in cohort 5.

Cabozantinib plus atezolizumab demonstrated clinical benefit in all groups. The objective response rate was 20%, 30% and 10% in cohorts 3, 4 and 5, respectively. One patient in cohort 3 (3%) and two patients in cohort 4 (7%) achieved a complete response. Median overall survival was approximately 14 months in cohorts 3 and 4 and eight months in cohort 5.

The most common treatment-related side effects were diarrhea, aspartate aminotransferase increase, decreased appetite, alanine aminotransferase increased, fatigue and nausea. Grade 3 or 4 side effects, which can be more severe, were reported by 63%, 43% and 45% of cohorts 3, 4 and 5, respectively.

Early results show efficacy of acalabrutinib in patients with marginal zone lymphoma

Results from a clinical trial of acalabrutinib in patients with relapsed or refractory marginal zone lymphoma will be presented at this year’s ASCO (Free ASCO Whitepaper) meeting in a poster session on Saturday, June 4, at 8 a.m. CDT.

Marginal zone lymphomas are a type of B cell non-Hodgkin lymphoma. Few treatment options are available for patients whose disease reappears after a period of remission, known as a relapse, or in those whose lymphoma does not respond to treatment, known as refractory.

Acalabrutinib is a potent next-generation Bruton tyrosine kinase (BTK) inhibitor. These inhibitors block an enzyme in a signaling pathway involved in the growth and survival of some B cell leukemias and lymphomas. BTK inhibitors have been shown to have durable responses in patients with relapsed or refractory marginal zone lymphoma.

Acalabrutinib monotherapy is being studied in a Phase 2 clinical trial at City of Hope and other comprehensive cancer centers across the country. In the trial, patients received 100 mg of acalabrutinib twice daily until their disease progressed or they experienced negative effects.

"Our early results indicate that acalabrutinib is efficacious and well-tolerated in patients with relapsed or refractory marginal zone lymphoma," said Elizabeth Budde, M.D., Ph.D., City of Hope associate professor, Division of Lymphoma, Department of Hematology & Hematopoietic Cell Transplantation, and the abstract’s lead author. "We now have data from 42 patients who were treated through October 2021, and all of them tolerated the therapy well."

The overall response rate in the 37 patients in whom this outcome measure could be evaluated was 54%. Of those patients, six had a complete response, 14 had partial responses and 17 patients had stable disease.

Most side effects were mild. Sixteen patients experienced side effects of grade 3 or higher, most commonly anemia, shortness of breath, fatigue, and reduced numbers of white blood cells, platelets and neutrophils. Two patients discontinued treatment because of serious side effects.

The study concluded that acalabrutinib is a promising treatment in patients with relapsed or refractory marginal zone lymphoma, which is considered incurable when it recurs.

Racial differences in the mutational landscape of serous endometrial cancer

Racial disparities persist in outcomes of endometrial cancer, the most common form of uterine cancer. To identify genetic differences in tumors that may contribute to worse prognosis, a team at Cancer Treatment Centers of America (CTCA), part of City of Hope, has analyzed comprehensive genomic profiling data from a large series of patients with serous endometrial cancer. The team is led by Julian Schink, M.D., chief medical officer of CTCA.

Tumors have genetic changes unique to an individual patient that can be targeted for therapy as part of a precision medicine approach. The 2022 National Comprehensive Cancer Network (NCCN) Guidelines for uterine neoplasms recommend genetic evaluation of tumors as part of the initial evaluation of a patient. In this study, the team analyzed data from 86 patients, of whom 37% were white, 58% were Black and 5% were Asian.

Schink and his team found genetic alterations in 94% of the patients. TP53 mutations, which are characteristic of serous cancer, were present in 93% of the patients.

However, they noted some racial differences in the genomic alterations identified. Alterations that are predicted to activate the phosphatidylinositol 3-kinase signaling pathway, which regulates cell proliferation and survival, were significantly more common in white women than in Black women (41% vs. 16%). These alterations included mutations in the genes PIK3CA, PIK3R1 and PTEN.

Amplification of CCNE1 was also noted more often in Black women, although this difference was not statistically significant.

"PIK3CA mutations are an important factor in resistance to anti-HER2 therapy, a treatment that targets the HER2 protein. Also, increased CCNE1 amplification has been linked to the racial disparities seen in cancer outcomes," said Schink, the abstract’s lead author. "Thus, identifying these racial differences in genomic alterations may help to explain the disparities we see with endometrial cancer and better inform therapy selection."

Study data on abstract 5600 will be presented in a poster session at the ASCO (Free ASCO Whitepaper) conference on Saturday, June 4, beginning at 1:15 p.m. CDT.

Initial findings for Nous-209 cancer vaccine combined with pembrolizumab

A promising off-the-shelf cancer vaccine called Nous-209 is being studied at City of Hope in patients with dMMR/MSI-H tumors (defective DNA mismatch repair/high microsatellite instability). These tumors have abnormalities that affect a cell’s ability to repair DNA, resulting in an accumulation of errors in a tumor’s genetic sequences.

Initial clinical outcomes in 20 patients enrolled in the Phase 1 study of Nous-209 in combination with the immune checkpoint inhibitor pembrolizumab will be presented in a poster discussion session at the ASCO (Free ASCO Whitepaper) conference on Sunday, June 5, at 11:42 a.m. CDT. Pembrolizumab is an antibody that blocks a protein called programmed death receptor-1 (PD-1). Marwan Fakih, M.D., City of Hope’s Judy & Bernard Briskin Distinguished Director of Clinical Research and professor, Department of Medical Oncology & Therapeutics Research, is the abstract’s lead author.

"The combination of the NOUS-209 cancer vaccine and pembrolizumab continues to be found to be safe and highly immunogenic," Fakih said. "Our promising findings for the early and long-term clinical efficacy of this combination may be attributable to the vaccine contribution."

Patients in the trial had dMMR/MSI-H colorectal, gastric or gastro-esophageal junction tumors that were metastatic or could not be removed with surgery. The drug combination was tested as a second-line therapy in patients whose disease had progressed despite prior treatment and as a first-line therapy in patients who refused or were ineligible for chemotherapy. None of the patients had previously been treated with pembrolizumab.

Investigators assessed tumor responses to the drug combination using the RECIST v1.1 guidelines. To date, 10 patients have shown a durable partial response to treatment, four showed durable stable disease and six showed progressive disease. Four of the six patients who showed disease progression did not receive the full vaccination schedule.

Nous-209 plus pembrolizumab was well tolerated and had a favorable safety profile. The most common treatment-related adverse events were nausea, diarrhea and fatigue, in 35%, 25% and 25% of the patients, respectively.

dMMR/MSI tumors carry tumor-specific frameshift peptides, which are produced as the result of the errors in the tumor’s DNA sequence. The Nous-209 vaccine carries the instructions to target 209 different frameshift peptides that dMMR/MSI tumors have in common. A tumor in any one patient will share 50 frameshift peptides on average with the Nous-209 vaccine. Thus, a patient’s own anti-tumor immune response can be activated after vaccination with Nous-209.

Future analyses are planned to further test the efficacy of Nous-209 and explore endpoints, such as the quality of the patient’s T cell responses to the vaccine.

City of Hope oncology chair receives prestigious ASCO (Free ASCO Whitepaper) award and experts serve on ASCO (Free ASCO Whitepaper) panels discussing health equity, cancer and aging, CAR T cell therapy and supportive care

Ravi Salgia, M.D., Ph.D, City of Hope’s Arthur & Rosalie Kaplan Chair in Medical Oncology, will receive the Excellence in Teaching Award on Saturday, June 4 at 1:34 p.m. CDT.

Edward Kim, M.D., M.B.A., physician-in-chief, City of Hope Orange County, and vice physician-in-chief, City of Hope National Medical Center, will speak on an education session titled "Expanding Clinical Trial Eligibility to Improve Their Generalizability and Advance Equity" on Sunday, June 5, at 9:45 a.m. CDT.

William Dale, M.D, Ph.D., City of Hope’s Arthur M. Coppola Family Chair in Supportive Care Medicine, will speak on a geriatric oncology education session to discuss early integration of palliative medicine for locally advanced and metastatic genitourinary malignancies on Sunday, June 5, at 4:48 p.m. CDT.

Tanya Dorff, M.D., City of Hope’s section chief, Genitourinary Disease Program, will speak on a case-based panel titled "CAR T for Prostate Cancer: Current Strategies to Improve Efficacy" on Monday, June 6, at 9:00 a.m. CDT.

Richard T. Lee, M.D., medical director of City of Hope’s Integrative Medicine Program, will serve on a panel titled "Highlights of the Care Delivery and Regulatory Policy Track" on Tuesday, June 7, at 9:12 a.m. CDT.

On May 27, 2022 Ambrx Biopharma Inc., or Ambrx, (NYSE: AMAM), a clinical stage biopharmaceutical company using an expanded genetic code technology platform to create Engineered Precision Biologics (EPBs), reported that Feng Tian, Ph.D., Chairman of the Board, President and CEO of Ambrx, will participate in two upcoming investor conferences in June (Press release, Ambrx, MAY 27, 2022, View Source [SID1234615208]).

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Cowen’s 3rd Annual Oncology Innovation Summit. Dr. Tian will participate in an analyst led fireside chat on Thursday, June 2 at 11:30 AM Pacific Time / 2:30 PM Eastern Time.

JMP Securities Life Sciences Conference. Dr. Tian will present on Thursday, June 16 at 11:00 AM Pacific Time / 2:00 PM Eastern Time.

Interested parties can access the live and pre-recorded webcasts for these conferences from the Investor Relations section of the company’s website at www.Ambrx.com. The webcast replays will be available after the conclusion of the respective presentations for approximately 90 days.

On May 27, 2022 iOnctura SA, a clinical-stage oncology company targeting key resistance mechanisms in solid tumours, reported that it will present at the 2022 ASCO (Free ASCO Whitepaper) (American Society of Clinical Oncology) Annual Meeting, taking place June 3-7 in Chicago, new interim Phase I data from completed study Part A and ongoing study Part B showing stable disease and improved overall survival compared to historical controls, with IOA-244 treatment (Press release, iOnctura, MAY 27, 2022, View Source [SID1234615207]).

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"We observed, in patients who progressed on prior therapies, that IOA-244 stabilized their disease and halted the progression after we had exhausted all prior therapies," said Dr Jeff Evans, Professor of Translational Cancer Research and Clinical Lead of the Institute of Cancer Sciences, University of Glasgow (UK). "We are pleased to be offering patients such a well-tolerated therapeutic candidate with potentially meaningful clinical benefit."

"Life expectancy in metastatic UM patients refractory to immunotherapy is severely limited: These patients have a median survival of just 7.2 months. Patients receiving the Recommended Phase 2 Dose of IOA-244 in the DIONE-01 study have already demonstrated a median treatment time exceeding this and encouragingly, the majority of patients are continuing on treatment," said Catherine Pickering, PhD, CEO of iOnctura. "The data in this study also show that daily oral IOA-244 has potentially best-in-class tolerability, which has allowed us to continue treating patients without the need for dose alterations. Based on these highly encouraging data in this Orphan indication, and with the full support of our current investors, we are now focusing on raising our Series B venture financing to fuel future development of IOA-244 and the other anti-cancer resistance products in our pipeline"

DIONE-01 is a two-part, first-in-human dose-escalation study evaluating oral IOA-244 in advanced metastatic cancers and as a combination partner for conventional and immune-therapies (ClinicalTrials.gov: NCT04328844). The objective of Part A, now complete, was to determine the safety, tolerability, the biologically effective dose range and consequently the dosage of IOA-244 in solid tumor cancer patients. The subsequent and continuing Part B of the study consists of expansion cohorts of patients with different solid tumor types, including patients with metastatic UM.

The poster presented at ASCO (Free ASCO Whitepaper) by lead author, Prof. Anna Maria Di Giacomo, Department of Medical Oncology, University Hospital of Siena, Italy, shows interim Phase I data in refractory UM patients, confirming safety and tolerability observed in Part A as well as longer than expected overall survival (OS). This OS trend is also being observed in subsequent Part B. Together and across both parts 16 UM patients have been treated to date. The one-year OS rate was 66.7% for patients in Part A (n=9). It is still too early to estimate the 1-year OS rate in Part B (n=7); at 6-months the OS rate is 100%. Significant reduction of Tregs in peripheral blood and tumor tissue was observed confirming the expected mechanism of action of a precision targeted PI3Kδ inhibitor.

"IOA-244 is a therapy which appeals to our patients, who come from various parts of the country. It allows patients to stay at home while receiving a well-tolerated and potentially effective treatment." added Professor Maio, Department of Medical Oncology, University Hospital of Siena, Italy. "We are eager to explore in greater detail the mechanism of action of IOA-244, its contribution in modulating T regulatory cells in cancer patients and applying new imaging approaches to document the effects of this novel immunotherapy."

Details of the presentation:

Title: First-in-human (FIH) phase I study of the highly selective phosphoinositide 3-kinase inhibitor delta (PI3Kδ) inhibitor IOA-244 in patients with advanced cancer: Safety, activity, pharmacokinetic (PK), pharmacodynamic (PD) results.
Type: Poster
Session: Developmental Therapeutics-Molecularly Targeted Agents and Tumor Biology
Time: Sunday, June 5, 2022, 8:00 AM-11:00 AM CDT
PI3Kδ and IOA-244

High expression of PI3Kδ in both cancer cells and in the tumor immune landscape is a contributing factor to many solid tumor types escaping the host’s immune response. This is achieved by tumors, in part, through PI3kδ-mediated upregulation of T regulatory (Treg) cells, making the tumors "cold", or difficult to detect by the body’s immune system. IOA-244 selective inhibition of PI3kδ blocks proliferation of Treg cells, thus making "cold" tumors "hot", unveiling them to immune system detection and facilitating an anti-tumour immune response.

Exquisite selectivity for PI3Kδ over other PI3 Kinase subtypes, including the closely related PI3Kγ, taken together with IOA-244’s unique semi-allosteric mechanism, which is achieved through differentiated binding to the PI3kδ protein’s kinase domain, represents a unique first-in-class mechanism in solid tumors. This mechanism may allow IOA-244 to lock the kinase in its resting state, preventing initiation of downstream cell signalling pathways normally triggered when it is activated at the cell membrane. The Company is investigating whether IOA-244’s semi-allosteric non-ATP competitive mechanism may block Treg upregulation and simultaneously avoid affecting other signalling cascades that may lead to toxicities. Other PI3kδ inhibitors are thought to act on PI3kδ by blocking the ATP pocket without preventing the kinase from being activated at the cell membrane.

Uveal melanoma (UM) is a rare malignancy arising within the uveal tract of the eye. There are approximately 7,000 newly diagnosed cases of uveal melanoma each year (around 2,000 in the United States). Over 50% of patients will progress to metastatic disease. Median overall survival for metastatic patients refractory to immunotherapy, the population included in the DIONE-01 trial, is approximately 7 months.