Working…
ClinicalTrials.gov
ClinicalTrials.gov Menu

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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03997968
Recruitment Status : Recruiting
First Posted : June 25, 2019
Last Update Posted : August 12, 2021
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 as a monotherapy and in combination with chemotherapy 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. Upon identification of the RP2D in the monotherapy, the study will open to three combination treatment arms to identify the RP2D in combination with rituximab and bendamustine in Non-Hodgkin Lymphoma and capecitabine or gemcitabine for solid tumors. 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 21-day or 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.

Layout table for study information
Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 320 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 2022


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

Drug: CYT-0851
Combination arm patients will receive CYT-0851 in combination with chemotherapy
Other Name: Gemcitabine

Drug: CYT-0851
Combination arm patients will receive CYT-0851 in combination with anti-CD20 antibody and chemotherapy
Other Names:
  • Rituximab
  • Bendamustine




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

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Layout table for eligibility information
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. Male or female ≥18 years of age at time of informed consent.

    1. Female subjects of childbearing potential must be non-lactating, not pregnant as confirmed by a negative serum pregnancy test at most 30 days before enrollment and within 72 hours before the first administration of CYT-0851
    2. Female subjects of childbearing potential must not donate ova during the study and for at least 90 days after the last dose of study drug and must agree to continue using an effective method of contraception during the screening period to first study drug administration until 90 days after the last dose of study drug
    3. Male subjects who have not had a vasectomy must agree to use an effective method of contraception during the study and until 90 days after the last dose of the study drug, and to not donate sperm during the study and for at least 90 days after the last dose of study drug
  2. ECOG Performance Status of 0-1
  3. Measurable disease defined by disease-specific response criteria
  4. Histologically-proven B cell malignancies, meeting the following criteria:

    1. Relapsed, refractory B-cell non-Hodgkin lymphoma requiring therapy, after at least two prior therapies, and if transplanted, then at least 3-month post autologous stem cell transplant and if CART-treated, then evidence of progression no sooner than 3 months post CART treatment, or
    2. Relapsed, refractory chronic lymphocytic leukemia requiring therapy after at least two prior therapies, including BTK and BCL-2 inhibitor therapy (unless ineligible for such therapy), or
    3. For multiple myeloma, relapsed or progressive on or after treatment with at least three prior therapies that included a proteasome inhibitor, an imide, daratumumab, and if transplant eligible, a bone marrow transplant (unless unfit for transplant), or
  5. Histologically-proven solid tumor meeting the following criteria:

    1. Patients must have failed, refused, or not be eligible for further standard therapies (including chemotherapy, hormonal therapies, Her-2 directed therapies, as appropriate) expected to provide clinical benefit, and meeting the following criteria
    2. Metastatic breast cancer (including ER/PR positive or negative, Her-2 positive and negative, triple negative), treated with at least 1 prior therapy for metastatic disease, or
    3. Recurrent squamous cell carcinoma of the head and neck (HNSCC) (dose escalation) or human papilloma virus positive (HPV+) HNSCC (dose-escalation and backfill), treated with at least 1 prior therapy, or
    4. Ovarian cancer, progressive after treatment with at least prior platinum-based chemotherapy, and therapy with a PARP inhibitor or
    5. Soft tissue sarcoma, treated with at least one line of prior systemic therapy, or
    6. Recurrent metastatic or locally advanced pancreatic cancer after first line chemotherapy (backfill patients only) or
    7. Histologically-proven advanced small-cell lung cancer (SCLC) (backfill patients only).

      1. Patients with mixed histology are not allowed
      2. Prior treatment with platinum containing chemotherapy regimen with no evidence of progression within 90 days of last dose of platinum agent and anti-PD-(L)1 unless contraindicated
      3. At least 1 prior line of chemotherapy, but no more than 3 prior lines of therapy
  6. Understands the procedures and requirements of the study and provides written informed consent and authorization for protected health information disclosure
  7. Willing and able to comply with the requirements of the study protocol
  8. Site of disease amenable to a biopsy and willing to undergo biopsy required for backfill, or for dose-escalation if considered unsafe (approval to participate in the study required by the Medical Monitor) provide an archival sample ≤ 12 months old

Key Phase 2 Inclusion Criteria

  1. Male or female ≥18 years of age at time of informed consent.

    1. Female subjects of childbearing potential must be non-lactating, not pregnant as confirmed by a negative serum pregnancy test at most 30 days before enrollment and within 72 hours before the first administration of CYT-0851
    2. Female subjects of childbearing potential must not donate ova during the study and for at least 90 days after the last dose of study drug and must agree to continue using, an effective method of contraception during the screening period to first study drug administration until 90 days after the last dose of study drug
    3. Male subjects who have not had a vasectomy must agree to use an effective method of contraception during the study and until 90 days after the last dose of the study drug, and to not donate sperm during the study and for at least 90 days after the last dose of study drug
  2. ECOG Performance Status of 0-1
  3. Measurable disease defined by disease-specific response criteria
  4. Site of disease amenable to a biopsy and willing to undergo a biopsy for the determination of biomarker status, or, if considered unsafe (approval to participate in the study required by the Medical Monitor), archival sample ≤ 12 months old for determination of biomarker status.
  5. Biomarker positive on recent biopsy or bone marrow sample if required for the specific cohort.
  6. Histologically-proven B cell malignancies, meeting the following criteria:

    1. DLBCL Cohort

      1. Histologically-documented DLBCL or double hit lymphoma (B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and Burkitt lymphoma with BCL2 and MYC translocations (WHO Classification)
      2. Progressing on or after treatment with at least two prior lines of therapy, including R-CHOP or equivalent first line therapy
      3. If transplanted, then at least 3-month post autologous stem cell transplant
      4. If CART-treated, then evidence of progression no sooner than 3 months post CART treatment
    2. MCL Cohort

      1. Histologically-documented MCL
      2. Any stage at diagnosis
      3. Progressing on or after treatment with at least 2 prior lines of therapy, including a Bruton tyrosine kinase (BTK) inhibitor, after a 14-day washout period
    3. Multiple Myeloma Cohort 1) Relapsed or progressing after treatment with at least 3 prior therapies that include a proteasome inhibitor, an Immunomodulatory imide drug (IMiD), daratumumab, and, if transplant eligible, a bone marrow transplant (unless unfit for transplant)
  7. Or Histologically-proven solid tumors meeting the following criterial

    1. Patients must have failed, refused, or not be eligible for further standard therapies (including chemotherapy, hormonal therapies, Her-2 directed therapies, as appropriate) expected to provide clinical benefit, and meeting the following criteria
    2. Triple Negative Breast Cancer Cohort

      1. Histologically-documented triple negative breast cancer, ER/PR negative (defined as <10% of cells expressing hormonal receptors via immunohistochemistry (IHC) analysis), and HER2-negative, defined as either of the following by local laboratory assessment:

        • In situ hybridization (ISH) non-amplified (ratio of HER2 to CEP17 < 2.0 or single probe average HER2 gene copy number < 4 signals/cell), or
        • IHC 0 or IHC 1+
      2. At least 1 prior line of chemotherapy, but no more than 5 prior lines of chemotherapy
    3. Ovarian Cancer Cohort

      1. Histologically-proven metastatic epithelial ovarian cancer
      2. Prior treatment with a platinum containing chemotherapy regimen
      3. Prior treatment with PARP inhibitor, and, unless in adjuvant setting, responsive to PARP inhibitor, with progression on or following PARP inhibitor treatment
      4. At least 1 prior line of therapy, but no more than 5 prior lines of chemotherapy
    4. Pancreatic Cancer Cohort 1) Histologically-proven metastatic or locally advanced pancreatic cancer 2) At least 1 prior line of chemotherapy but no more than 4 prior lines of systemic therapy
    5. Soft Tissue Sarcoma Cohort

      1. Histologically-proven advanced soft-tissue sarcoma excluding all types of adipocytic sarcoma and GIST
      2. At least 1 prior line of systemic therapy (unless no standard of care exists), but no more than 5 prior lines of systemic therapy
  8. Follicular Lymphoma Cohort

    1. Histologically-documented follicular lymphoma
    2. Relapsed, refractory follicular lymphoma requiring therapy, after at least two prior therapies, and if CART-treated, then evidence of progression no sooner than 3 months post CART treatment
  9. Understands the procedures and requirements of the study and provides written informed consent and authorization for protected health information disclosure
  10. Willing and able to comply with the requirements of the study protocol

Key Exclusion Criteria

  1. Medical Conditions

    1. Known history of HIV
    2. Known history of viral hepatitis B unless HBV viral load is below the limit of quantification and off viral suppressive therapy
    3. Know history of hepatitis C unless antiviral treatment with curative intent completed and HCV viral load is below the limit of quantification.
    4. Myocardial infarction or stroke within 6 months
    5. Uncontrolled hypertension (systolic blood pressure (SBP) > 160 or diastolic blood pressure (DBP) >100 on maximal medical therapy)
    6. History of interstitial pulmonary disease
    7. Unresolved pneumonitis
    8. Grade ≥ 3 neuropathy
    9. Known active central nervous system (CNS) metastases. Subjects with previously treated CNS metastases may participate as long as clinically and radiologically stable for at least 4 weeks after treatment, have no evidence of new or enlarging lesions and are off steroids and asymptomatic for 28 days prior to dosing with study medication
    10. Known history of meningeal involvement or meningeal carcinomatosis
    11. Spinal cord compression not definitively treated with surgery and/or radiation, or previously diagnosed and treated spinal cord compression without evidence that disease has been clinically stable for > 2 weeks prior to screening visit
    12. Presence of clinically significant cataracts
    13. Second malignancy, except treated basal cell or localized squamous skin carcinomas, localized prostate cancer, or other malignancy that is in remission or stable and for which patients have not been on active anti-cancer therapy for 2 years
    14. Pregnant or lactating. If β-HCG is elevated, eligible if ultrasound confirms absence of a pregnancy.
    15. Dementia or significantly altered metal status
  2. Prior/Concomitant Therapy

    a. Prior allogeneic stem cell transplant b. On systemic antibiotic, antifungal or anti-viral therapy c. White blood cell (WBC) growth factors administered within 14 days of screening visit d. Cancer therapy within 14 days prior to treatment with study drug e. On narrow therapeutic index medications (see Section 7.6.1 for list of drugs) that are sensitive substrates of CYP3A, P-gp or BCRP (or caution is warranted with approval by the Sponsor).

    f. On any drug known to prolong QTc interval (eg, certain antiarrhythmic, antimicrobials) that cannot be discontinued or interrupted 72 hours before the Day 1 dose through Day 2, and 72 hours before the Day 15 dose until Day 16 (BID dosing) or the Day 22 dose until Day 23 (QD dosing), in Cycle 1 (see Section 7.6.1 for a list of drugs).

    g. On systemic corticosteroid treatment for non-tumor indication at a daily dose equivalent to >10mg of Prednisone

  3. Prior/Concurrent Clinical Study Experience

    a. Participation in another clinical trial (unless in the observation phase, or an observational study), or exposure to any investigational agent within 14 days prior to treatment with study drug

  4. Laboratory assessments

    1. Complete blood count (CBC):

      Monotherapy and Chemotherapy Combinations 1 and 2:

      1. ANC < 1.0 × 10^9/L
      2. PLT < 75 × 10^9/L
      3. Hgb < 9.0 g/dL

        Chemotherapy Combination Group 3:

      1) ANC < 1.5 × 10^9/L 2) PLT < 100 × 10^9/L 3) Hgb < 9.0 g/dL

      Monotherapy and Chemotherapy Combination Groups 1 and 2:

    2. Calculated Creatinine clearance (Cockcroft-Gault) < 40 mL/min

Chemotherapy Combination Group 3:

b. Calculated Creatinine clearance (Cockcroft-Gault) < 50 mL/min c. Hepatic function

  1. AST > 2.0 × ULN
  2. ALT > 2.0 × ULN d. Total bilirubin > 1.5 x ULN e. Albumin < 2.8 g/dL 5. ECG Exclusion a. Screening QTc interval > 450 milliseconds for males and QTc > 470 ms for females (corrected by Fridericia) 6. Other Exclusions

    1. Unwilling or unable to make all planned study visits
    2. Unwilling or unable to provide a recent biopsy or bone marrow sample prior to enrollment and during study; Note: certain exceptions may be permitted allowing archival specimens prior to treatment or for subjects where a specimen is not required for biomarker positive testing (see Sections 6.1.9.1 and 6.2.8)
    3. Significant medical diseases or conditions, as assessed by the Investigators and Cyteir that would substantially increase the risk-benefit ratio of participating in the study. This includes but is not limited to acute myocardial infarction, arterial thrombosis, significant gastrointestinal bleed, or unstable angina within the last 6 months uncontrolled diabetes mellitus, current active infections, severely immunocompromised state, and congestive heart failure New York Heart Association (NYHA) Class III-IV, left ventricular ejection fraction (LVEF) < 40% d: Chemotherapy Combination Group 3 only: known history of dhydropyrimidine dehydrogenase deficiency

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
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
Publications of Results:
Layout table for additonal information
Responsible Party: Cyteir Therapeutics, Inc.
ClinicalTrials.gov Identifier: NCT03997968    
Other Study ID Numbers: CYT-0851-01
First Posted: June 25, 2019    Key Record Dates
Last Update Posted: August 12, 2021
Last Verified: August 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Layout table for additional information
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:
Layout table for MeSH terms
Lymphoma
Breast Neoplasms
Multiple Myeloma
Neoplasms
Sarcoma
Lymphoma, Mantle-Cell
Small Cell Lung Carcinoma
Triple Negative Breast Neoplasms
Squamous Cell Carcinoma of Head and Neck
Neoplasms by Histologic Type
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Neoplasms by Site
Breast Diseases
Skin Diseases
Carcinoma, Squamous Cell
Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms, Plasma Cell
Hemostatic Disorders
Vascular Diseases
Cardiovascular Diseases
Paraproteinemias
Blood Protein Disorders
Hematologic Diseases
Hemorrhagic Disorders
Lymphoma, Non-Hodgkin
Neoplasms, Connective and Soft Tissue