On December 12, 2022 Actinium Pharmaceuticals, Inc. (NYSE AMERICAN: ATNM) (Actinium or the Company) a leader in the development of targeted radiotherapies, reported high rates of Complete Remission (CR/CRi) and rates of measurable residual disease (MRD) negativity with improved overall survival in its Actimab-A CLAG-M combination trial in high-risk patients with relapsed or refractory (r/r) acute myeloid leukemia (AML) (Press release, Actinium Pharmaceuticals, DEC 12, 2022, View Source [SID1234625154]). These data were detailed in an oral presentation at the 64th Annual ASH (Free ASH Whitepaper) Meeting & Symposium being held December 10-13, 2022 in New Orleans, Louisiana. The trial enrolled patients with intermediate and adverse cytogenetics including over 50% with a TP53 mutation and significant prior treatment with a median of 2 lines of therapy and over 57% having prior Venetoclax based therapy. The addition of Actimab-A to CLAG-M was well tolerated with expected toxicities.

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Dr. Sameem Abedin, Assistant Professor at Froedtert & Medical College Wisconsin and Principal Investigator of the Study, commented, "The high rates of MRD negativity and strong survival outcomes, especially in the TP53 mutant and Venetoclax treated patients, is highly encouraging and represents a significant improvement compared to available therapies for these patients. The patients enrolled on this trial have very difficult to treat AML and a dismal prognosis with an expected survival of 2 to 3 months or less. They also have very limited treatment options. High rates of 1-year survival are rare in these patients and 2-year survival is rarely achieved. With Venetoclax treatment becoming standard of care, it is critical that we find a therapy for the high percentage of patients who do not respond or relapse and therapies with better outcomes for all relapsed or refractory patients. Outside of this novel clinical trial, these patients would not have been considered for CLAG-M treatment as it would not be expected to have this type of effect in patients who had failed venetoclax based on our considerable prior experience with this regimen. Importantly, the combination was well tolerated with manageable toxicities and enabled a significant number of patients to proceed to transplant. These data support advancing the Actimab-A CLAG-M combination in a registration enabling study."

Overall Survival
Patients

12-month Overall Survival

24-month Overall Survival

All (n=23)

53 %

32 %

CRc MRD Negative (n=9)

89 %

48 %

TP53 mutation (n=13)

51 %

19 %

Prior Venetoclax (n=13)

59 %

32 %

1st/2nd Salvage (n=14)

61 %

49 %

Dr. Avinash Desai, Actinium’s Chief Medical Officer, commented, "As a first-in-class targeted radiotherapy, Actimab-A represents a novel treatment for patients with relapsed or refractory AML. Its differentiated mechanism of action attacks leukemia cells with a radioactive payload that the cancer cells have never been exposed to, which we believe is driving improved outcomes in these heavily pretreated and adverse cytogenetic patients. The high rates and deep remissions evidenced by the 75% measurable residual disease negativity are exciting and support the hypothesis of this combination. We are thrilled to show improved survival, especially in the TP53 mutant and Venetoclax treated patients who have dismal outcomes with expected survival of less than 3 months and few, if any, treatment options. With enrollment of this study complete, we look forward to leveraging the strong survival, MRD negativity and complete remission results to rapidly establish an efficient development and regulatory strategy."

MRD Negativity and Response Rates
MRD negativity was 75% in patients achieving CRc, assessed by multiparametric flow cytometry.
Response

Recommended Phase
2 Dose (n=8)

Prior Venetoclax
Therapy (n=13)

All Patients

(n=23)

CR

13 %

15 %

22 %

CRi

50 %

15 %

30 %

CRc (CR/CRi)

63 %

31 %

52 %

Bridged to BMT

50 %

75 %

64 %

Patient Characteristics
Patients received a median of two lines of prior therapy (Range: 1 – 5 lines)
57% received prior treatment with Venetoclax
67% of patients had adverse cytogenetics, 52% had TP53 mutations
52% of patients had secondary AML or treatment related AML

References:

1) Maiti et al. Outcomes of relapsed or refractory acute myeloid leukemia after front-line hypomethylating agent and venetoclax regimens. Hematoligica 2021 Mar 1; 894-898

2) Ganzel et al. Very poor long-term survival in past and more recent studies for relapsed AML patients: The ECOG-ACRIN experience. American Journal of Hematology. 2018 Aug; 93(8): 1074–1081

On December 12, 2022 IDEAYA Biosciences, Inc. (NASDAQ: IDYA), a synthetic lethality focused precision medicine oncology company committed to the discovery and development of targeted therapeutics, reported that it has submitted an Investigational New Drug (IND) application with the U.S. Food and Drug Administration (FDA) for initiation of a Phase 1/2 clinical trial to evaluate IDE161, a small molecule inhibitor of poly (ADP-ribose) glycohydrolase (PARG), for the treatment of patients having solid tumors with homologous recombination deficiency (HRD) (Press release, Ideaya Biosciences, DEC 12, 2022, View Source [SID1234625153]).

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"IDE161 has an attractive preclinical profile, including single-agent tumor regressions in PARP inhibitor-resistant BRCA1/2 xenograft models, and a favorable preliminary preclinical myelosuppression safety profile relative to certain approved PARP inhibitors. The IND submission for IDE161 is a significant milestone for IDEAYA and reflects our unique platform capabilities in synthetic lethality for target and biomarker identification, and drug discovery," said Michael White, Ph.D., Senior Vice President and Chief Scientific Officer, IDEAYA Biosciences.

"There remains a significant unmet medical need for patients having tumors with homologous recombination deficiencies, such as BRCA1/2, and IDE161 has a potential opportunity for clinical differentiation in patients who are non-responsive to PARP inhibitors or to platinum-based treatments," said Dr. Darrin M. Beaupre, M.D., Ph.D., Senior Vice President and Chief Medical Officer, IDEAYA Biosciences.

IDE161 is a potent, selective, potential first-in-class small-molecule inhibitor of PARG, a novel and differentiated target in the same clinically validated pathway as poly (ADP-ribose) polymerase (PARP). Subject to effectiveness of the IND following FDA review, IDEAYA plans to evaluate the safety, tolerability, pharmacokinetic and pharmacodynamic properties and preliminary efficacy of IDE161 as monotherapy in BRCA1/2-mutant breast and ovarian cancer patients.

IDEAYA owns or controls all commercial rights in IDE161, subject to certain economic obligations pursuant to its exclusive, worldwide license with Cancer Research UK and University of Manchester.

Additional information on IDE161, including scientific insights and clinical development opportunities, will be highlighted in an Investor R&D Day webcast being hosted by IDEAYA this morning, December 12, 2022, at 8:00 am – 9:30 am ET. Registration is available at View Source or View Source

On December 12, 2022 Asieris Pharmaceuticals (688176), a global biopharma company specializing in discovering, developing and commercializing innovative drugs for the treatment of genitourinary tumors and other related diseases,reported that the first patient enrolled in phase II clinical study of oral APL-1202 in combination with PD-1 inhibitor Tislelizumab as neoadjuvant therapy for muscular invasive bladder cancer (MIBC) (Press release, Asieris Pharmaceuticals, DEC 12, 2022, View Source [SID1234625152]).

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This is an open-label, multi-center Phase I/II clinical study with the following objectives: to evaluate the safety in MIBC patients, to determine the recommended Phase 2 dose (RP2D), and to assess efficacy as neoadjuvant therapy for MIBC.

The investigational new drug (IND) application was approved by the U.S. Food and Drug Administration (FDA) in June and the Center for Drug Evaluation (CDE) of the National Medical Products Administration of China in October 2021. The first patient was dosed in December of the same year. The trial completed the phase I dose-escalation trial and proceed to phase II in November 2022.

APL-1202 is an orally available reversible MetAP2 Inhibitor with anti-angiogenic, anti-tumor activities and can also modulate tumor immune microenvironment. It is currently in registration clinical trials in China, either as single agent as first-line treatment for patients with intermediate-risk non-muscle invasive bladder cancer (NMIBC), or in combination with a chemotherapy as second-line treatment in patients with intermediate and high-risk chemo-refractory NMIBC.

Tislelizumab is BeiGene’s humanized IgG4 anti-PD-1 monoclonal antibody specifically designed to minimize binding to FcγR on macrophages. The China National Medical Products Administration (NMPA) has approved Tislelizumab in nine indications and recently accepted a supplemental biologics application for tislelizumab in combination with chemotherapy as a first-line (1L) treatment in patients with unresectable locally advanced, recurrent or metastatic esophageal squamous cell carcinoma. Tislelizumab is the first investigational medicine from BeiGene’s immuno-oncology biologics program and is being evaluated in solid tumor and hematologic malignancies, as monotherapy and in combination.The global tislelizumab clinical development program includes more than 11,000 subjects enrolled to-date in 30 countries and regions.

"APL-1202 in combination with Tislelizumab has shown a promising safety profile in the phase I stage of the clinical trial," commented Dr. John Zhuang, Chief Operation Officer at Asieris. "We will further explore the efficacy and safety of the combination in this phase II stage, and continue to make positive progress on the clinical development of the neoadjuvant therapy to address unmet medical needs and benefit more patients."

On December 12, 2022 CellCentric, a privately owned, clinical stage biotechnology company pioneering small molecule inhibition of p300/CBP to treat cancer, reported clinical data for the first time at the 64th American Society of Haematology (ASH) (Free ASH Whitepaper) Annual Meeting, New Orleans (Press release, CellCentric, DEC 12, 2022, View Source [SID1234625151]).

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To date, 26 patients with relapsed/refractory multiple myeloma (RRMM) have been treated with inobrodib as monotherapy, including seven most recently at the recommended phase 2 dose and dose schedule (RP2D). Treatment has been generally well-tolerated with the majority of on-target toxicities being mild or moderate in severity.

Among the patients treated at the RP2D, six out of seven patients had reduction or stabilisation of serum free light chains. One patient saw an unconfirmed Complete Response (CR), which went on to become a durable confirmed Very Good Partial Response (VGPR); a second patient demonstrated a confirmed Partial Response (PR); and a third currently has an unconfirmed PR (by IMWG response criteria). These three patients remain on treatment after more than eight months.

Dose escalation in combination with pomalidomide and dexamethasone has been initiated in heavily pre-treated RRMM patients. Despite all three initial patients being pomalidomide-refractory, all showed a degree of response after the first cycle of treatment: 1 VGPR, 1 PR and 1 MR (serum M-protein 34% decrease).

Tim Somervaille, the Chief Investigator of Study CCS1477-02, CellCentric’s Phase 1 / 2, international haematological malignancy study, and Professor of Haematological Oncology at Cancer Research UK Manchester Institute and The University of Manchester, and Honorary Consultant Haematologist at The Christie NHS Foundation Trust said: "We are excited with these initial clinical results, which show inobrodib has the potential to offer patients with advanced multiple myeloma an additional treatment option. Furthermore, the preclinical data also presented today outlines and supports the hypothesis that targeting p300/CBP with inobrodib represents an entirely novel therapeutic strategy in this disease setting. Taken together, these findings provide clear encouragement for the further clinical development of this first in class drug."

Paul Richardson, Director of Clinical Research and Clinical Program Leader of the Jerome Pippe Myeloma Center and the RJ Corman Professor of Medicine, Harvard Medical School and Dana Farber Cancer Institute added: "This is encouraging early progress in a relapsed and refractory myeloma patient population that has significant unmet medical needs. Demonstrating clear monotherapy activity is important, but so too is seeing promising initial signs of combinability with existing standards of care, which typically serve as backbone agents in this setting."

Leif Bergsagel, Professor of Medicine for the Mayo Clinic College of Medicine, and a consultant in the Division of Hematology and Medical Oncology, Department of Internal Medicine, at Mayo Clinic, Arizona said: "Inobrodib has an interesting, new mode of action, and importantly is also an oral agent. Ease of use is a key consideration as we look for the widest adoption of new treatments in the community."

Presentation details

Potent Pre-Clinical and Early Phase Clinical Activity of EP300/CBP Bromodomain Inhibitor CCS1477 in Multiple Myeloma

Session Name: 651. Multiple Myeloma and Plasma Cell Dyscrasias: Basic and Translational
Session Date, Time: Saturday, December 10, 2022, 4:00 PM
Room: Ernest N. Morial Convention Center, New Orleans Theater C
Publication Number: 349

About inobrodib:

CellCentric has developed inobrodib from concept through to clinical trials. It is an oral, first in class small molecule inhibitor drug that targets twin cancer gene regulators p300 and CBP. Inhibiting p300/CBP impacts the expression of key cancer drivers including MYC and IRF4 which are particularly important in the progression of certain blood cancers. In addition, inobrodib impacts the androgen receptor pathway. CellCentric has demonstrated that its pioneering drug, inobrodib, has a direct impact on these key oncogenes both pre-clinically and in tumour samples.

Inobrodib is formulated as an oral capsule which, along with its manageable safety profile, allows for administration at home.

As well as testing in heavily pre-treated, relapsed refractory haematological malignancy patients, CellCentric also has a study evaluating inobrodib in solid tumours, including late stage prostate cancer (mCRPC).

On December 12, 2022 Xencor, Inc. (NASDAQ: XNCR), a clinical-stage biopharmaceutical company developing engineered antibodies and cytokines for the treatment of cancer and autoimmune diseases, reported additional clinical data from expansion cohorts in its Phase 1 study of plamotamab, a CD20 x CD3 bispecific antibody, in patients with relapsed or refractory non-Hodgkin lymphomas (Press release, Xencor, DEC 12, 2022, View Source [SID1234625150]). Data will be presented by Krish Patel, M.D., Director of the Lymphoma Program at Swedish Cancer Institute, in a poster session today from 6:00 p.m. to 8:00 p.m. CST at the 64th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting in New Orleans, Louisiana.

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"Patients with non-Hodgkin lymphomas need further therapy options which can be efficacious, well-tolerated and importantly, administered in a variety of settings," said Dr. Patel. "In the Phase 1 monotherapy study of plamotamab, the recommended intravenous dose was well tolerated, and we are encouraged by the responses observed in the study. This was a cohort of patients that were heavily pretreated, enriched with adverse prognostic factors, and included poor risk histology, such as high-grade B cell lymphoma and activated B-cell DLBCL."

"Our strategy is to develop plamotamab as part of multiple highly active chemotherapy-free regimens across B-cell cancers. Xencor’s first combination study, evaluating plamotamab with tafasitamab plus lenalidomide, is enrolling patients with advanced, aggressive lymphoma. Importantly, we are engineering novel B-cell targeted CD28 bispecific antibodies that may selectively enhance T-cell cytotoxic activity," said Allen Yang, M.D., Ph.D., senior vice president and chief medical officer at Xencor. "Additionally, patients enrolling to the ongoing Phase 1 monotherapy study will now receive subcutaneous doses of plamotamab."

At data cut off on August 24, 2022, 44 patients with relapsed or refractory non-Hodgkin lymphoma (NHL) had been enrolled before June 30, 2022 and received the recommended dose. Patients had a median age of 69 years and had received a median of 4 prior therapies. At baseline, 86% had advanced stage III or IV disease. Additionally, 50% of patients received CAR-T as a prior therapy.

The primary disease at enrollment for these patients was diffuse large B-cell lymphoma (DLBCL; n=26), high-grade B-cell lymphoma (HGBCL; n=6), follicular lymphoma (FL; n=10), and other lymphoma (n=2).

Safety Analysis

The safety profile of plamotamab was consistent with previous results. The most common Grade 3 or 4 treatment-emergent adverse events (AEs) across all patients were neutropenia (25.0%), anemia (15.9%) and lymphopenia (11.4%). Grade 3 immune effector cell-associated neurotoxicity syndrome was observed in one patient (2.3%). AEs leading to plamotamab discontinuation occurred in nine patients (20.5%), including four patients (9.1%) who discontinued due to COVID-19. Cytokine release syndrome (CRS), the most common AE, was observed in 70.5% of patients, and no patients experienced Grade 3 or 4 CRS.

Efficacy Analysis

The efficacy analysis included both evaluable and intent-to-treat (ITT) patient populations. Responses were assessed based on the Lugano Classification.

In the efficacy evaluable population of patients with DLBCL or HGBCL, the overall response rate (ORR) was 52.0% (13/25), and the complete response rate was 24.0% (6/25). For patients who received prior CAR-T therapy, the ORR was 50.0% (8/16), and the CR rate was 25.0% (4/16). In the ITT population, the ORR was 43.8% (14/32), and the complete response rate was 18.8% (6/32). The median duration of response (mDOR) for both populations was 126 days.

In the efficacy evaluable population of patients with FL, the ORR was 87.5% (7/8), and the CR rate was 50.0% (4/8). In the ITT population, the ORR was 80.0% (8/10), and the CR rate was 40.0% (4/10). The mDOR for both populations had not been reached.

Dose Exposure-Response Analysis

An analysis of the plamotamab exposure-response (ER) relationship from the dose-escalation portion of the Phase 1 study examined IL-6 levels, CRS incidence, high-grade AEs and overall response. First-dose CRS was related to maximum plamotamab concentration (Cmax). The probability of CRS with step-up dosing, however, was better modeled using the magnitude of the step-up increment, as measured by the ratio of Cmax after dosing to the concentration prior to that dosing (Ctrough). Once the target dose was reached, there was no relationship of exposure to high-grade CRS. This analysis indicates the potential for a wide therapeutic window at the target dose and provides guidance for improving dosing regimens in future clinical studies of plamotamab.

The poster will be archived under "Events & Presentations" in the Investors section of the Company’s website located at www.xencor.com.

About Plamotamab

Plamotamab is an investigational tumor-targeted XmAb bispecific antibody that contains both a CD20 binding domain and a cytotoxic T-cell binding domain (CD3). CD20 is highly expressed across a range of B-cell tumors, including non-Hodgkin lymphoma (NHL). Engagement of CD3 by plamotamab activates T cells for highly potent and targeted killing of CD20-expressing tumor cells.

Safety and anti-tumor activity from the ongoing Phase 1 clinical study has indicated that plamotamab was generally well tolerated and demonstrated encouraging clinical activity as a monotherapy. Plamotamab is also being evaluated in a Phase 2 study, in combination with tafasitamab plus lenalidomide, in patients with relapsed or refractory diffuse large B-cell lymphoma. The study consists of two parts, a safety run-in intended to establish the safety of the triple combination and a two-arm, open-label cohort where patients will be randomized to receive either the triple combination or tafasitamab plus lenalidomide.

Xencor has entered an exclusive collaboration and worldwide license agreement with Janssen Biotech, Inc. (Janssen) to develop and commercialize plamotamab and novel XmAb B-cell targeting bispecific antibodies that are designed to conditionally activate T cells through co-stimulation.