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A Phase 1/2 Study of CYT-0851, an Oral RAD51 Inhibitor, in B-Cell Malignancies and Advanced Solid Tumors

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ClinicalTrials.gov Identifier: NCT03997968
Recruitment Status : Not yet recruiting
First Posted : June 25, 2019
Last Update Posted : June 25, 2019
Sponsor:
Information provided by (Responsible Party):
Cyteir Therapeutics, Inc.

Brief Summary:
This clinical trial is an interventional, active-treatment, open-label, multi-center, Phase 1/2 study. The study objectives are to assess the safety, tolerability and pharmacokinetics (PK) of the oral RAD51 inhibitor CYT-0851 in patients with relapsed/refractory B-cell malignancies and advanced solid tumors and to identify a recommended Phase 2 dose for evaluation in these patients.

Condition or disease Intervention/treatment Phase
Malignancy Non-hodgkin Lymphoma Multiple Myeloma Breast Cancer Ovarian Cancer Soft Tissue Sarcoma Squamous Cell Carcinoma Head and Neck Cancer DLBCL Mantle Cell Lymphoma Follicular Lymphoma Leiomyosarcoma Pancreatic Cancer Sarcoma CLL Drug: CYT-0851 Phase 1 Phase 2

Detailed Description:

Overexpression of activation-induced cytidine deaminase (AID) or other cytidine deaminases causes high rates of deoxyribonucleic acid (DNA) damage (mutations, double strand DNA breaks, and chromosome rearrangements) in a high number of patients with B-cell malignancies, such as NHL, MM, and CLL, and in a subset of patients with solid tumors, such as non-small cell lung cancer (NSCLC), sarcoma, breast cancer, ovarian cancer, and squamous cell carcinoma of the head and neck. Cancer cells that overexpress AID and other cytidine deaminases rely on RAD51, a protein involved in homologous recombination, to repair the DNA damage caused by cytidine deaminases. Inhibition of RAD51 with CYT-0851 in preclinical models induces cell death, tumor growth delay or tumor regression.

The Phase 1 part of the study will follow an accelerated titration design, which includes enrollment of single patient cohorts until certain criteria are met, followed by a standard 3+3 design. This design will allow for identification of a recommended phase 2 dose (RP2D) level while dosing the least number of patients as possible at potentially sub-therapeutic doses. In the Phase 2 part of the study, preliminary efficacy will be evaluated in 6 expansion cohorts (total n = 60-136), using a Simon two-stage design. The RP2D will be selected based on the MTD, the safety profile, PK, and available pharmacodynamics data generated from all subjects in Phase 1.

In both Phase 1 and Phase 2, patients will be treated in continuous 28-day cycles and all patients will be assessed for response every 2 cycles. Treatment will be terminated if the patient progresses, cannot tolerate treatment, or withdraws consent from active therapy. Patients will undergo a safety evaluation approximately 1 month (28-35 days) after the last dose. Patients will be followed for response until progression is documented.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 165 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Multi-Center, Open Label Phase 1/2 Study of CYT-0851, an Oral RAD51 Inhibitor, in Patients With Relapsed/Refractory B-Cell Malignancies and Advanced Solid Tumors
Estimated Study Start Date : September 2019
Estimated Primary Completion Date : September 2021
Estimated Study Completion Date : October 2021


Arm Intervention/treatment
Experimental: Experimental: Active treatment
This is an open label study. All patients will receive single agent CYT-0851 administered orally.
Drug: CYT-0851
All patients will receive CYT-0851 as a single agent




Primary Outcome Measures :
  1. Dose limiting Toxicity [ Time Frame: Phase 1: 12 months; ]
    Identify nature and frequency of dose limiting toxicities

  2. Overall Response Rate [ Time Frame: 24 Months ]
    Percent of Patients responding to treatment


Secondary Outcome Measures :
  1. Adverse Events [ Time Frame: 24 months ]
    • Evaluate the safety of CYT-0851
    • Establish the PK of CYT-0851 Evaluate the type and frequency of adverse events

  2. Blood CYT-0851 concentrations [ Time Frame: Phase 1: 12 months ]
    Measure CYT-0851 concentrations over time

  3. Duration of Response [ Time Frame: 24 months ]
    For responders, time from response to progression

  4. Overall survival [ Time Frame: 24 months ]
    Time from treatment start to death

  5. Progression-free survival [ Time Frame: 24 months ]
    Time from treatment start to progression or death

  6. Laboratory and ECG abnormalities [ Time Frame: 24 months ]
    Percentage of grade of laboratory and ECG abnormalities



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Key Phase 1 Inclusion Criteria

  1. ECOG Performance Status of 0-1
  2. Measurable disease
  3. Willing to undergo a tumor biopsy
  4. Histologically-proven B cell malignancies, meeting the following criteria:

    1. Relapsed, refractory B-cell non-Hodgkin lymphoma requiring therapy
    2. Relapsed, refractory chronic lymphocytic leukemia requiring therapy
    3. For multiple myeloma, relapsed or progressive on or after treatment with at least three prior therapies
  5. Histologically-proven solid tumor meeting the following criteria:

    1. Metastatic breast cancer
    2. Recurrent squamous cell carcinoma of the head and neck
    3. Ovarian cancer
    4. Soft tissue sarcoma
    5. Recurrent metastatic or locally advanced pancreatic cancer
  6. Willing to provide a fresh biopsy (unless considered unsafe) after cycle 1 and a blood sample for determination of biomarker status.

Key Phase 2 Inclusion Criteria

  1. ECOG Performance Status of 0-1
  2. Measurable disease defined by disease-specific response criteria
  3. Site of disease amenable to a biopsy and willing to undergo a biopsy
  4. Biomarker positive on recent biopsy or blood sample
  5. Histologically-proven B cell malignancies, meeting the following criteria: DLBCL, MCL, or Multiple Myeloma requiring therapy
  6. Histologically-proven solid tumors: Triple Negative Breast Cancer , Ovarian Cancer or biomarker positive cancers

Key Exclusion Criteria

  1. Known history of brain metastases, unless treated (Phase 1 only) with whole brain radiation, off steroids, and stable over at least past 2 months documented on serial MRI scans.
  2. Known history of meningeal involvement or meningeal carcinomatosis
  3. Spinal cord compression not definitively treated with surgery and/or radiation
  4. Laboratory assessments

    1. ANC < 1.0 x 109/L; PLT < 75 x 109/L; Hgb < 9.0 g/dL
    2. Calculated Creatinine clearance (Cockcroft-Gault) < 60 mL/min
    3. Hepatic function: AST > 2.0 x ULN; ALT > 2.0 x ULN; Total bilirubin > 1.5 ; Albumin < 2.8 g/dL
  5. Screening QTc interval > 480 milliseconds (corrected by Fridericia)

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03997968


Contacts
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Contact: Markus Renschler, MD (857) 285-4142 clinicaltrials@cyteir.com
Contact: Todd Bowser, PhD 857 626 4694 clinicaloperations@cyteir.com

Sponsors and Collaborators
Cyteir Therapeutics, Inc.
Investigators
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Study Director: Markus Renschler, MD Cyteir Therapeutics

Publications of Results:
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Responsible Party: Cyteir Therapeutics, Inc.
ClinicalTrials.gov Identifier: NCT03997968     History of Changes
Other Study ID Numbers: CYT-0851-01
First Posted: June 25, 2019    Key Record Dates
Last Update Posted: June 25, 2019
Last Verified: June 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Cyteir Therapeutics, Inc.:
Oral RAD51-inhibitor; refractory; B-cell; solid tumor
DNA Damage Repair inhibitor
cancer

Additional relevant MeSH terms:
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Lymphoma
Carcinoma, Squamous Cell
Multiple Myeloma
Lymphoma, Follicular
Pancreatic Neoplasms
Neoplasms
Sarcoma
Lymphoma, Non-Hodgkin
Head and Neck Neoplasms
Lymphoma, Mantle-Cell
Leiomyosarcoma
Neoplasms by Histologic Type
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms, Squamous Cell
Neoplasms, Plasma Cell
Hemostatic Disorders
Vascular Diseases
Cardiovascular Diseases
Paraproteinemias
Blood Protein Disorders
Hematologic Diseases
Hemorrhagic Disorders
Digestive System Neoplasms
Neoplasms by Site
Endocrine Gland Neoplasms