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.
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
Drug | Synonyms | Arms |
---|
CYT-0851 | | Experimental: 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
Name | Type | Description | Interventions |
---|
Experimental: Active treatment | Experimental | This is an open label study. All patients will receive single agent CYT-0851 administered orally. | |
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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