Clinical Trials /

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

NCT03997968

Description:

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.

Related Conditions:
  • B-Cell Non-Hodgkin Lymphoma
  • Breast Carcinoma
  • Chronic Lymphocytic Leukemia
  • Diffuse Large B-Cell Lymphoma
  • Head and Neck Squamous Cell Carcinoma
  • Malignant Solid Tumor
  • Mantle Cell Lymphoma
  • Multiple Myeloma
  • Ovarian Carcinoma
  • Pancreatic Carcinoma
  • Soft Tissue Sarcoma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

URL:

https://clinicaltrials.gov/show/NCT03997968

Trial Eligibility

Document

Title

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

Clinical Trial IDs

  • ORG STUDY ID: CYT-0851-01
  • NCT ID: NCT03997968

Conditions

  • 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

Interventions

DrugSynonymsArms
CYT-0851Experimental: Active treatment

Purpose

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.

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.

Trial Arms

NameTypeDescriptionInterventions
Experimental: Active treatmentExperimentalThis is an open label study. All patients will receive single agent CYT-0851 administered orally.
  • CYT-0851

Eligibility 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. Relapsed or progressive multiple myeloma on or after treatment

          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

        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 bone marrow 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) .

          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 10^9/L; PLT < 75 x 10^9/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 > 450 milliseconds (males) and > 470 ms for females
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Dose limiting Toxicity
Time Frame:Phase 1: 12 months;
Safety Issue:
Description:Identify nature and frequency of dose limiting toxicities

Secondary Outcome Measures

Measure:Adverse Events
Time Frame:24 months
Safety Issue:
Description:Evaluate the safety of CYT-0851 Establish the PK of CYT-0851 Evaluate the type and frequency of adverse events
Measure:Blood CYT-0851 concentrations
Time Frame:Phase 1: 12 months
Safety Issue:
Description:Measure CYT-0851 concentrations over time
Measure:Duration of Response
Time Frame:24 months
Safety Issue:
Description:For responders, time from response to progression
Measure:Overall survival
Time Frame:24 months
Safety Issue:
Description:Time from treatment start to death
Measure:Progression-free survival
Time Frame:24 months
Safety Issue:
Description:Time from treatment start to progression or death
Measure:Laboratory and ECG abnormalities
Time Frame:24 months
Safety Issue:
Description:Percentage of grade of laboratory and ECG abnormalities

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Cyteir Therapeutics, Inc.

Trial Keywords

  • Oral RAD51-inhibitor; refractory; B-cell; solid tumor
  • DNA Damage Repair inhibitor
  • cancer

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