On December 11, 2024 EORTC and Immunocore reported the randomisation of the first patient in the Phase 3 Adjuvant Trial in Ocular Melanoma (ATOM), investigating the safety and efficacy of tebentafusp as adjuvant treatment for uveal melanoma (Press release, EORTC, DEC 11, 2024, View Source [SID1234649044]).

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The primary objective of the open-label, international, multicentre trial – led by EORTC – will be to assess whether tebentafusp can prevent or delay relapse in patients with primary ocular (uveal) melanoma at high risk of relapse, as compared with observation. Tebentafusp is approved for the treatment of HLA-A*02:01-positive adult patients with unresectable or metastatic uveal melanoma in 38 countries, under the brand name KIMMTRAK.

"I am delighted that the first patient on ATOM has been recruited. This milestone reflects a very significant effort by the EORTC melanoma group trials team, colleagues at Immunocore and our trial sites," said Professor Paul Nathan, ATOM study coordinator. "The study addresses a key question – whether the benefit seen with tebentafusp in HLA-A*02:01-positive patients with metastatic uveal melanoma will translate to a significant reduction in risk of relapse for patients who have received treatment for primary uveal melanoma and are at high risk of relapse."

The trial is expected to enrol 290 HLA-A*02:01-positive patients with uveal melanoma who have undergone definitive treatment by surgery or radiotherapy. Eligible patients will be randomised 1:1 to one of two arms: tebentafusp [as monotherapy] for six months or until disease relapse, or observation. Secondary objectives include overall survival, safety and tolerability, while exploratory objectives include evaluation of circulating tumour DNA (ctDNA) as a marker of residual disease, and a comparison of health-related quality of life.

Mohammed Dar, Chief Medical Officer at Immunocore, said: "Despite definitive local therapy, approximately 50% of patients will eventually relapse with metastatic disease. The goal of investigating adjuvant tebentafusp following primary treatment is to prevent future recurrence. Decreasing the likelihood of a patient relapsing following definitive therapy for their primary disease would be a groundbreaking advancement in treatment, given there are currently no standard treatment options available in this setting."

About the ATOM Phase 3 trial
ATOM (NCT06246149; 2023-510333-28-00) is an EORTC-led randomised open-label international multicentre Phase 3 superiority clinical trial aiming to prospectively assess whether adjuvant treatment with tebentafusp improves relapse-free survival as compared with observation. A total of 290 patients are expected to be enrolled within a span of three years, beginning in 13 countries, and with the potential for further expansion.

The goal of the experimental treatment strategy in the trial is to establish whether adjuvant tebentafusp can decrease the risk of relapse – compared to observation – in patients who have undergone definitive treatment for primary uveal melanoma and who are at high risk of relapse.

Patients included in the study must have undergone definitive treatment for primary ocular melanoma, by surgery or radiotherapy; be at high risk of relapse; be HLA-A*02:01 positive; have a good performance status (ECOG 0/1); and adequate organ function. Eligible patients will be randomised 1:1 to receive either active treatment with weekly tebentafusp [as monotherapy], or observation. Patients will receive tebentafusp for 6 months, or until relapse.

The secondary objectives are to compare overall survival and to further document the safety and tolerability of tebentafusp.

The exploratory objectives include the comparison of the health-related quality of life between the treatment arms and the evaluation of the role of circulating tumour DNA (ctDNA) as a biomarker for the presence of residual disease.

About Uveal Melanoma
Uveal melanoma is a rare disease arising from the pigmented uveal tract of the eye with an estimated incidence in Europe of 4.4 cases per million [i]. Up to 50% of people with uveal melanoma will eventually develop metastatic disease [ii]. Metastases usually appear within a median of three to five years after treatment of primary tumours, and treatment of metastatic disease is usually with palliative intent. Unresectable or metastatic uveal melanoma typically has a poor prognosis and had no approved treatment until KIMMTRAK.

Very few studies have tested the use of adjuvant treatment in uveal melanoma, and none have resulted in any change in the standard of care, reflecting a lack of active agents for this disease.

[i] Virgili G, Gatta G, Ciccolallo L, Capocaccia R, Biggeri A, Crocetti E, et al. Incidence of Uveal Melanoma in Europe. Ophthalmology 2007.
View Source

[ii] Shields CL, Furuta M, Thangappan A, Nagori S, Mashayekhi A, Lally DR, et al. Metastasis of uveal melanoma millimeter-by-millimeter in 8033 consecutive eyes. Arch Ophthalmol 2009.
View Source

About ImmTAC molecules for cancer
Immunocore’s proprietary T cell receptor (TCR) technology generates a novel class of bispecific biologics called ImmTAC (Immune mobilizing monoclonal TCRs Against Cancer) molecules that are designed to redirect the immune system to recognise and kill cancerous cells. ImmTAC molecules are soluble TCRs engineered to recognize intracellular cancer antigens with ultra-high affinity and selectively kill these cancer cells via an anti-CD3 immune-activating effector function. Based on the demonstrated mechanism of T cell infiltration into human tumours, the ImmTAC mechanism of action holds the potential to treat hematologic and solid tumours, regardless of mutational burden or immune infiltration, including immune "cold" low mutation rate tumours.

On December 11, 2024 iOnctura, a clinical-stage biopharmaceutical company combating neglected and hard-to-treat cancers, reported a clinical update on its lead asset, roginolisib. Results from the completed Phase I DIONE-01 study are due to be presented at the European Society for Medical Oncology Immuno-Oncology (ESMO-IO) annual congress tomorrow, 12 December at 12:30 CET (presentation 164P) (Press release, iOnctura, DEC 11, 2024, View Source [SID1234649059]).

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Allosteric modulator of PI3Kδ, roginolisib, has a unique chemical structure and binding mechanism which makes it highly specific for PI3Kδ, giving it an advantageous pharmacology profile and an unprecedented safety profile compared to previous generations of PI3Kδ inhibitors.

Roginolisib is being investigated in solid and hematological malignancies including uveal melanoma (UM), a rare cancer of the eye. Eye melanoma is a rapidly growing market which is projected to be worth USD 9.56B by 2032[1].

The two-part Phase I study DIONE-01, firstly evaluated continuous daily dosing of roginolisib [at 10, 20, 40 and 80 mg] in 24 patients with pretreated solid tumors and follicular lymphoma (FL), and secondly evaluated a dose confirmation cohort in 20 UM patients.

Results from DIONE-01 show:

Study met its primary objective to determine the safety of the anticipated optimal biologically effective dose (BED): Roginolisib was well tolerated at the recommended Phase II dose (RP2D) of 80mg, with <7% Grade 3/4 treatment-emergent adverse events (TEAEs) considered to be related to roginolisib. TEAEs did not result in immune-related toxicity, or dose-limiting toxicity, in either solid tumor or hematological patients. In contrast to prior PI3Kδ inhibitors, roginolisib dosing did not require dose modifications.
Roginolisib is well tolerated over long periods of treatment, up to 4.5 years.
Median overall survival (OS) was 16 months for the 29 patients with UM treated with roginolisib, who had previously received a median of two prior therapies. This exceeds the median OS of 7 months observed in historical controls in patients receiving immunotherapies as second line treatment[2].
Median progression free survival (PFS) was 5 months for patients treated with roginolisib versus less than 3 months for historical controls2.
Clinical findings validate the mechanism of action of roginolisib: roginolisib reduces immune-suppressive immune cells and chemokines, UM-related tumor clones (ctDNA) and PI3K-related signaling indicating a rebalancing of the immune system.
Catherine Pickering, Chief Executive Officer of iOnctura, said: "The Phase I DIONE-01 data highlight the benefits of roginolisib for patients with uveal melanoma and advanced cancers. Roginolisib’s unique allosteric binding mechanism has translated into a differentiated beneficial clinical profile, including a doubling of overall survival compared to historical controls in uveal melanoma. We are delighted to announce these data support progression of roginolisib into a randomized Phase II study."

Professor Michele Maio, University of Siena and Principal Investigator of the roginolisib studies, added: "Being able to continue to investigate roginolisib in a randomized Phase II study is a positive step to understand more about this already well tolerated molecule. Roginolisib has given prolonged disease stabilization to patients with uveal melanoma who have exhausted all other therapeutic options. So far, these patients have maintained a good quality of life without major limitations. I’m looking forward to seeing what the Phase II trial delivers over the coming months."

Activation of trial sites for the Phase II OCULE-01 study (NCT06717126) investigating roginolisib versus investigator’s choice in the second-line+ treatment of uveal melanoma is ongoing.

On December 10, 2024 Cellectis (Euronext Growth: ALCLS – NASDAQ: CLLS) (the "Company"), a clinical-stage biotechnology company using its pioneering gene-editing platform to develop life-saving cell and gene therapies, reported that it has drawn down the final tranche of €5 million ("Tranche C") under the credit facility agreement for up to €40 million entered into with the European Investment Bank (the "EIB) on December 28, 2022 (the "Finance Contract") (Press release, Cellectis, DEC 10, 2024, View Source [SID1234648976]). With the drawdown of Tranche C, the Company has drawn down the full €40 million available under the Finance Contract. Tranche C is expected to be disbursed by the EIB by December 18, 2024. The Company plans to use the proceeds of Tranche C towards the development of its pipeline of allogeneic CAR T-cell product candidates: UCART22 and UCART20x22.

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As a condition to the disbursement of Tranche C the Company issued 611,426 warrants to the benefit of the EIB, in accordance with the terms of the 14th resolution of the shareholders’ meeting held on June 28, 2024 and articles L. 228-91 and seq. of the French Commercial Code (the "Tranche C Warrants").

Each Tranche C Warrant allows the EIB to subscribe for one ordinary share of the Company, at a price of €1.70, corresponding to 99% of the volume-weighted average price of the Company’s ordinary shares over the last 3 trading days preceding the decision of the board of directors of the Company to issue the Tranche C Warrants. The total number of shares issuable upon exercise of the Tranche C Warrants represent circa 0.6% of the Company’s outstanding share capital as at their issuance date.

Tranche C will mature six years from its disbursement date and will accrue interest at a rate of 6% per annum capitalized annually and payable at maturity.

The other terms of the Tranche C Warrants and prepayment events of Tranche C under the Finance Contract are as set forth in the Company’s press release of April 4, 2023 and Form 6-K filed with the U.S. Securities and Exchange Commission on such date.

On December 9, 2024 Protara Therapeutics, Inc. (Nasdaq: TARA) ("Protara"), a clinical-stage company developing transformative therapies for the treatment of cancer and rare diseases, reported the pricing of its underwritten public offering of 13,690,000 shares of its common stock at a price to the public of $6.25 per share and pre-funded warrants to purchase 2,325,372 shares of common stock at a price of $6.249 per pre-funded warrant, which represents the per share price for the common stock less the $0.001 per share exercise price for each such pre-funded warrant (Press release, Protara Therapeutics, DEC 10, 2024, View Source [SID1234648992]). In addition, Protara has granted the underwriters a 30-day option to purchase up to an additional 2,402,305 shares of common stock at the public offering price, less underwriting discounts and commissions. All shares and pre-funded warrants in the offering are being sold by Protara. The gross proceeds from the offering are expected to be approximately $100 million before deducting underwriting discounts and commissions and offering expenses payable by Protara and excluding any exercise of the underwriters’ option to purchase additional shares and the exercise of any pre-funded warrants. The offering is expected to close on December 11, 2024, subject to satisfaction of customary closing conditions. Protara intends to use the net proceeds received from the offering to fund the clinical development of TARA-002, as well as the development of other clinical programs. Protara may also use the net proceeds from the offering for working capital and other general corporate purposes.

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TD Cowen, Cantor, LifeSci Capital, Oppenheimer & Co. and Scotiabank are acting as joint book-running managers of the offering.

The shares of common stock and the pre-funded warrants will be issued pursuant to an effective shelf registration statement on Form S-3 (File No. 333-275290) that was declared effective on November 14, 2023 by the U.S. Securities and Exchange Commission (the "SEC"). The offering is being made only by means of a prospectus supplement and the accompanying prospectus. A final prospectus supplement relating to the offering will be filed with the SEC and will be available on the SEC’s website, located at www.sec.gov. Copies of the final prospectus supplement and the accompanying prospectus relating to the offering, when available, may be obtained from the offices of TD Securities (USA) LLC, 1 Vanderbilt Avenue, New York, New York 10017, by email at [email protected] or by telephone at (855) 495-9846; Cantor Fitzgerald & Co., 110 East 59th Street, 6th Floor, New York, New York 10022, Attention: Capital Markets, or by email at [email protected]; or LifeSci Capital LLC, 1700 Broadway, 40th Floor, New York, New York 10019, or by email at [email protected].

This press release shall not constitute an offer to sell or a solicitation of an offer to buy any of these securities, nor shall there be any sale of these securities in any state or jurisdiction in which such an offer, solicitation or sale would be unlawful prior to registration or qualification under the applicable securities laws of such state or jurisdiction.

On December 10, 2024 Ascentage Pharma (6855.HK), a global biopharmaceutical company engaged in discovering, developing, and commercializing therapies to address global unmet medical needs primarily for malignancies, reported that it has released the latest clinical data of lisaftoclax (APG-2575) as a monotherapy or in combinations in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), in a Poster Presentation at the 66th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting, taking place in San Diego, CA, the United States (Press release, Ascentage Pharma, DEC 10, 2024, View Source;ascentage-pharmas-bcl-2-inhibitor-lisaftoclax-in-combinations-demonstrates-potential-clinical-benefit-in-patients-with-prior-exposure-to-venetoclax-302327542.html [SID1234649008]). Dr. Matthew Davids, from Dana-Farber Cancer Institute in the US, is the principal investigator of the study.

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The ASH (Free ASH Whitepaper) Annual Meeting is one of the largest gatherings of the international hematology community, bringing together the most cutting-edge scientific research and latest data of investigational therapies that represent leading scientific and clinical advances in the global hematology field. Garnering growing interest from the global research community, results from multiple clinical and preclinical studies on four of Ascentage Pharma’s drug candidates (olverembatinib, lisaftoclax, APG-2449, and APG-5918) have been selected for presentations, including two Oral Reports, at this year’s ASH (Free ASH Whitepaper) Annual Meeting.

These data once again highlighted the therapeutic magnitude of Ascentage Pharma’s Bcl-2 selective inhibitor lisaftoclax, as a monotherapy and in combinations, in patients with relapsed/refractory (R/R) CLL/SLL, particularly the clinical benefit of lisaftoclax in combination with acalabrutinib in patients with prior exposure to venetoclax, including those who progressed on or were intolerant/refractory to venetoclax. Furthermore, no drug-drug interactions (DDIs) or new safety signals were observed in patients treated with lisaftoclax monotherapy or combinations.

Dr. Matthew S. Davids commented, "Lisaftoclax continues to demonstrate very strong efficacy in multiple patient subgroups, including those who previously progressed on venetoclax or BTK inhibitors. The drug also has excellent tolerability and the convenience of a daily dose ramp-up to reach the target effective dose. Based on the promising early phase results, the GLORA global registrational study has now launched and is actively enrolling."

"Results released at this year’s ASH (Free ASH Whitepaper) Annual Meeting reaffirmed the therapeutic potential of lisaftoclax in CLL/SLL," said Dr. Yifan Zhai, Chief Medical Officer of Ascentage Pharma. "In China, a New Drug Application (NDA) for lisaftoclax has already been accepted and granted the Priority Review designation by the Center for Drug Evaluation (CDE) of China’s National Medical Products Administration (NMPA), potentially leading lisaftoclax to become the second Bcl-2 inhibitor approved anywhere in the world. In the US, a global registrational Phase III study that was cleared by the US Food and Drug Administration (FDA) is currently underway. Fulfilling our mission of addressing unmet clinical needs in China and around the world, we will expedite the global clinical development of our key drug candidates such as lisaftoclax to bring more safe and effective therapies to patients as soon as possible."

Highlights of the data this study reported at ASH (Free ASH Whitepaper) 2024 are as below:

Lisaftoclax (APG-2575) Demonstrates Activity and Safety When Given With Accelerated Ramp-up and Then Combined With Acalabrutinib or Rituximab in Patients (pts) With Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL), Including Those With Prior Exposure to Venetoclax
Format: Poster Presentation
Abstract#: 4614
Session: 642. Chronic Lymphocytic Leukemia: Clinical and Epidemiological: Poster III

Highlights:

Background: Bcl-2 inhibition with venetoclax (ven) was a major advance in CLL treatment, but the 5-week dose ramp-up to mitigate the risk of tumor lysis syndrome (TLS) and DDIs challenge treatment optimization. Lisaftoclax is an investigational, oral Bcl-2i with a short half-life, allowing it to be ramped-up on a daily schedule.

Introduction: This poster presents updated clinical data of lisaftoclax alone or combined with acalabrutinib or rituximab in patients with treatment-naïve (TN), R/R, or prior ven-treated CLL/SLL.

Enrolled Patients and Study Methods:

From March 20, 2020, to June 27, 2024, 176 patients were enrolled: 46 in monotherapy and 39 and 91 in the rituximab and acalabrutinib combination cohorts, respectively; 87.5% (154/176) of patients were R/R and 12.5% (22/176) were TN. The median (range) age was 63 (34-80) years; 67% were male; 25.6% had del(17p) and/or TP53 mutation.
Median (range) duration of treatment with lisaftoclax was 16.5 (1-54; monotherapy), 24 (3-39; rituximab), and 27 (1-43; acalabrutinib) cycles. Fourteen (9%) patients relapsed on or were intolerant /refractory to prior treatment with ven. Their median (range) age was 65 (51-78) and 79% were male. 50% of those patients had del (17p), 36% had the TP53 mutation, 64% had del (11q), 38% had a complex karyotype (≥ 3 abnormalities), and 92% had unmutated IGHV.
Patients were treated with a rapid 4- to 6-day daily ramp-up of lisaftoclax from 20 mg to a target dose of 400, 600, or 800 mg, receiving daily oral lisaftoclax alone or, plus continuous acalabrutinib or 6 cycles of rituximab in 28-day cycles, starting on Cycle 1 Day 8 (C1D8) until disease progression, complete response by C24, or unacceptable toxicity.
Efficacy Results:

The ORR for lisaftoclax plus acalabrutinib in 87 patients was 98%, and the median duration of response (DOR; 95% CI, 31-NE) and median progression-free survival (PFS; 95% CI, 34-NE) of responders were not reached.

Among patients who received lisaftoclax plus acalabrutinib, 14 have relapsed on or were intolerant/refractory to prior treatment with ven. Their median (range) cycles of treatment were 16 (3-25), the ORR was 86%, the median PFS was not reached (11.3-NE), the 12-month PFS rate was 84%, and the 18-month PFS rate was 73%.
Among patients who received lisaftoclax plus acalabrutinib, 9 were refractory to ven. Their median (range) cycles of treatment were 16 (3-25), the ORR was 89%. The median PFS was not reached (NE-NE), the 12-month PFS rate was 89%, and the 18-month PFS rate was 89%.
Safety Results:

Incidence and severity of TEAEs were similar across cohorts.
Common (≥20%) any-grade TEAEs in all cohorts combined were infection (107 [61%]), neutropenia (67 [38%]), anemia (51 [29%]), diarrhea (51 [29%]), and thrombocytopenia (38 [22%]). Grade ≥ 3 treatment-emergent AEs (TEAEs；≥10%) were neutropenia in 15 (33%), 11 (28%), and 27 (30%) patients; infection in 13 (28%), 4 (10%), and 14 (15%) patients; and anemia in 8 (17%), 4 (10%), and 11 (12%) patients in monotherapy, rituximab, and acalabrutinib combination cohorts, respectively.
Lisaftoclax, alone or in combination, demonstrated a favorable safety profile and a rate of clinical tumor lysis syndrome (TLS) of 1.1%. No DDIs or new safety signals were observed in patients who received lisaftoclax in combination with acalabrutinib or rituximab.
Conclusions: The presented data suggest that lisaftoclax combined with acalabrutinib was active in patients with TN or R/R CLL, with a reported 98% ORR and a median DOR that was not reached at 22.3 months of median follow-up. Lisaftoclax combined with acalabrutinib was also effective for patients with prior ven exposure, including those who progressed on or were intolerant/refractory to ven. In this updated analysis with longer follow-up, no DDIs or new safety findings were observed in TN or R/R CLL/SLL patients treated with lisaftoclax monotherapy or combinations. Patients with prior ven exposure continue to be accrued in order to further evaluate this promising signal. A global registrational phase III study is recruiting.

*Lisaftoclax is an investigational drug that has not been approved in any country and region.