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

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

Study Description
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 Head and Neck Cancer DLBCL Mantle Cell Lymphoma Follicular Lymphoma Pancreatic Cancer CLL Small Cell Lung Cancer Squamous Cell Carcinoma of Head and Neck Triple Negative Breast Cancer 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 8 expansion cohorts (total n = 92-220), 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.

Study Design
Layout table for study information
Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 280 participants
Allocation: N/A
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
Actual Study Start Date : October 9, 2019
Estimated Primary Completion Date : September 2021
Estimated Study Completion Date : October 2021
Arms and Interventions
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
Outcome Measures
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


Eligibility Criteria
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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. 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
    6. Advanced small-cell lung 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 if required
  5. Histologically-proven B cell malignancies, meeting the following criteria: DLBCL, MCL, or Multiple Myeloma requiring therapy

  6. Histologically-proven solid tumors:

    1. Triple negative breast cancer
    2. Ovarian cancer
    3. Pancreatic cancer
    4. Soft tissue sarcoma
    5. Other biomarker positive cancers

Key Exclusion Criteria

  1. Known active brain metastases
  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) < 40 mL/min
    3. Hepatic function: AST > 2.0 x ULN; ALT > 2.0 x ULN;
    4. Total bilirubin > 1.5 x ULN;
    5. Albumin < 2.8 g/dL
  5. Screening QTc interval > 450 milliseconds (males) and > 470 ms for females
Contacts and Locations

Contacts
Layout table for location contacts
Contact: Judson Englert, MD 857-285-4140 clinicaltrials@cyteir.com
Contact: Susan Doleman 857-285-4140 clinicaloperations@cyteir.com

Locations
Show Show 18 study locations
Sponsors and Collaborators
Cyteir Therapeutics, Inc.
Investigators
Layout table for investigator information
Study Director: Judson Englert, MD Cyteir Therapeutics
Tracking Information
First Submitted Date  ICMJE June 24, 2019
First Posted Date  ICMJE June 25, 2019
Last Update Posted Date February 2, 2021
Actual Study Start Date  ICMJE October 9, 2019
Estimated Primary Completion Date September 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: June 24, 2019)
  • Dose limiting Toxicity [ Time Frame: Phase 1: 12 months; ]
    Identify nature and frequency of dose limiting toxicities
  • Overall Response Rate [ Time Frame: 24 Months ]
    Percent of Patients responding to treatment
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: June 24, 2019)
  • 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
  • Blood CYT-0851 concentrations [ Time Frame: Phase 1: 12 months ]
    Measure CYT-0851 concentrations over time
  • Duration of Response [ Time Frame: 24 months ]
    For responders, time from response to progression
  • Overall survival [ Time Frame: 24 months ]
    Time from treatment start to death
  • Progression-free survival [ Time Frame: 24 months ]
    Time from treatment start to progression or death
  • Laboratory and ECG abnormalities [ Time Frame: 24 months ]
    Percentage of grade of laboratory and ECG abnormalities
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE A Phase 1/2 Study of CYT-0851, an Oral RAD51 Inhibitor, in B-Cell Malignancies and Advanced Solid Tumors
Official Title  ICMJE 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
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.
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 8 expansion cohorts (total n = 92-220), 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.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Malignancy
  • Non-hodgkin Lymphoma
  • Multiple Myeloma
  • Breast Cancer
  • Ovarian Cancer
  • Soft Tissue Sarcoma
  • Head and Neck Cancer
  • DLBCL
  • Mantle Cell Lymphoma
  • Follicular Lymphoma
  • Pancreatic Cancer
  • CLL
  • Small Cell Lung Cancer
  • Squamous Cell Carcinoma of Head and Neck
  • Triple Negative Breast Cancer
Intervention  ICMJE Drug: CYT-0851
All patients will receive CYT-0851 as a single agent
Study Arms  ICMJE Experimental: Experimental: Active treatment
This is an open label study. All patients will receive single agent CYT-0851 administered orally.
Intervention: Drug: CYT-0851
Publications * Lamont KR, Hasham MG, Donghia NM, Branca J, Chavaree M, Chase B, Breggia A, Hedlund J, Emery I, Cavallo F, Jasin M, Rüter J, Mills KD. Attenuating homologous recombination stimulates an AID-induced antileukemic effect. J Exp Med. 2013 May 6;210(5):1021-33.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: January 28, 2021) 		280
Original Estimated Enrollment  ICMJE
 (submitted: June 24, 2019) 		165
Estimated Study Completion Date  ICMJE October 2021
Estimated Primary Completion Date September 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
    6. Advanced small-cell lung 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 if required
  5. Histologically-proven B cell malignancies, meeting the following criteria: DLBCL, MCL, or Multiple Myeloma requiring therapy

  6. Histologically-proven solid tumors:

    1. Triple negative breast cancer
    2. Ovarian cancer
    3. Pancreatic cancer
    4. Soft tissue sarcoma
    5. Other biomarker positive cancers

Key Exclusion Criteria

  1. Known active brain metastases
  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) < 40 mL/min
    3. Hepatic function: AST > 2.0 x ULN; ALT > 2.0 x ULN;
    4. Total bilirubin > 1.5 x ULN;
    5. Albumin < 2.8 g/dL
  5. Screening QTc interval > 450 milliseconds (males) and > 470 ms for females
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Judson Englert, MD 857-285-4140 clinicaltrials@cyteir.com
Contact: Susan Doleman 857-285-4140 clinicaloperations@cyteir.com
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03997968
Other Study ID Numbers  ICMJE CYT-0851-01
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Cyteir Therapeutics, Inc.
Study Sponsor  ICMJE Cyteir Therapeutics, Inc.
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Judson Englert, MD Cyteir Therapeutics
PRS Account Cyteir Therapeutics, Inc.
Verification Date January 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP

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