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

Overview

About this study

The purpose of this study is 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.

Participation eligibility

Participant eligibility includes age, gender, type and stage of disease, and previous treatments or health concerns. Guidelines differ from study to study, and identify who can or cannot participate. There is no guarantee that every individual who qualifies and wants to participate in a trial will be enrolled. Contact the study team to discuss study eligibility and potential participation.

Inclusion Criteria - Phase I:

  • Male or female ≥ 18 years of age at time of informed consent.
    • 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;
    • 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;
    • 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.
  • ECOG Performance Status of 0-1.
  • Measurable disease defined by disease-specific response criteria.
  • Histologically-proven B cell malignancies, meeting the following criteria:
    • 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
    • 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
    • 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 
  • Histologically-proven solid tumor meeting the following criteria:
    • 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;
    • 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
    • Recurrent squamous cell carcinoma of the head and neck (dose escalation) or HPV+ HNSCC (dose-escalation and backfill), treated with at least 1 prior therapy; or
    • Ovarian cancer, progressive after treatment with at least prior platinum-based chemotherapy, and therapy with a PARP inhibitor; or
    • Soft tissue sarcoma, treated with at least one line of prior systemic therapy; or
    • Recurrent metastatic or locally advanced pancreatic cancer after first line chemotherapy (backfill patients only);
    • Histologically-proven advanced small-cell lung cancer (backfill patients only):
      • Patients with mixed histology are not allowed;
      • 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;
      • At least 1 prior line of chemotherapy, but no more than 3 prior lines of therapy.
  • Understands the procedures and requirements of the study and provides written informed consent and authorization for protected health information disclosure.
  • Willing and able to comply with the requirements of the study protocol.
  • 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.

Inclusion Criteria - Phase 2:

  • ECOG Performance Status of 0-1.
  • Measurable disease defined by disease-specific response criteria.
  • Site of disease amenable to a biopsy and willing to undergo a biopsy.
  • Biomarker positive on recent biopsy or bone marrow sample.
  • Histologically-proven B cell malignancies, meeting the following criteria:
  • DLBCL Cohort
    • 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);
    • Progressing on or after treatment with at least two prior lines of therapy, including RCHOP or equivalent first line therapy;
    • If transplanted, then at least 3-month post autologous stem cell transplant;
    • If CART-treated, then evidence of progression no sooner than 3 months post CART treatment.
  • MCL Cohort
    • Histologically-documented MCL;
    • Any stage at diagnosis;
    • 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.
  • Multiple Myeloma Cohort
    • 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).
  • Or Histologically-proven solid tumors meeting the following criteria:
    • 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.
  • Triple Negative Breast Cancer Cohort
    • Histologically-documented triple negative breast cancer, ER/PR negative (defined as < 10% of cells expressing hormonal receptors via immuno-histochemistry (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+.
    • At least 1 prior line of chemotherapy, but no more than 5 prior lines of chemotherapy.
  • Ovarian Cancer Cohort
    • Histologically-proven metastatic epithelial ovarian cancer;
    • Prior treatment with a platinum containing chemotherapy regimen;
    • Prior treatment with PARP inhibitor, and, unless in adjuvant setting, responsive to PARP inhibitor, with progression on or following PARP inhibitor treatment;
    • At least 1 prior line of therapy, but no more than 5 prior lines of chemotherapy.
  • Pancreatic Cancer Cohort
    • Histologically-proven metastatic or locally advanced pancreatic cancer;
    • At least 1 prior line of chemotherapy but no more than 4 prior lines of systemic therapy.
  • Soft Tissue Sarcoma Cohort
    • Histologically-proven advanced soft-tissue sarcoma excluding all types of adipocytic sarcoma and GIST;
    • At least 1 prior line of systemic therapy (unless no standard of care exists), but no more than 5 prior lines of systemic therapy.
  • Or Biomarker positive cancers meeting the following criteria:
    • Histologically-documented hematologic malignancy, (excluding the histologies above);
    • Advanced or metastatic disease with at least 1 prior line of chemotherapy (2 prior lines of therapy for CLL, including BTK and BCL-2 inhibitor therapy (unless ineligible for such therapy) with evidence of progression on or following therapy, but no more than 6 lines of prior chemotherapy, and must have failed, refused or not be eligible for further standard therapies expected to provide clinical benefit.
  • Understands the procedures and requirements of the study and provides written informed consent and authorization for protected health information disclosure.
  • Willing and able to comply with the requirements of the study protocol.

Exclusion Criteria:

  • Known history of HIV.
  • Known history of viral hepatitis B unless HBV viral load is below the limit of quantification and off viral suppressive therapy.
  • Know history of hepatitis C unless antiviral treatment with curative intent completed and HCV viral load is below the limit of quantification.
  • Myocardial infarction or stroke within 6 months.
  • Uncontrolled hypertension (systolic blood pressure (SBP) > 160 or diastolic blood pressure (DBP) >100 on maximal medical therapy).
  • History of interstitial pulmonary disease.
  • Unresolved pneumonitis.
  • Grade ≥ 3 neuropathy.
  • 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.
  • Known history of meningeal involvement or meningeal carcinomatosis.
  • 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.
  • Presence of clinically significant cataracts.
  • 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.
  • Pregnant or lactating. If β-HCG is elevated, eligible if ultrasound confirms absence of a pregnancy.
  • Dementia or significantly altered metal status.
  • Prior allogeneic stem cell transplant.
  • On systemic antibiotic, antifungal or anti-viral therapy.
  • White blood cell (WBC) growth factors administered within 14 days of screening visit
  • Cancer therapy within 14 days prior to treatment with study drug.
  • On narrow therapeutic index medications that are sensitive substrates of CYP3A, P-gp or BCRP (or caution is warranted with approval by the Sponsor).
  • 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 Day 22 dose until Day 23 (QD dosing) , in Cycle 1
  •  g. On systemic corticosteroid treatment for non-tumor indication at a daily dose equivalent to > 10mg of Prednisone.
  • 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.
  • Laboratory assessments:
  • Complete blood count (CBC):
    • ANC < 1.0 × 10^9 /L;
    • PLT < 75 × 10^9 /L;
    • Hgb < 9.0 g/dL.
  • Calculated Creatinine clearance
    • (Cockcroft-Gault) < 40 mL/min.
  • Hepatic function
    • AST > 2.0 × ULN;
    • ALT > 2.0 × ULN.
  • Total bilirubin > 1.5 x ULN.
  • Albumin < 2.8 g/dL.
  • Screening QTc interval > 450 milliseconds for males and QTc > 470 ms for females (corrected by Fridericia).
  • Unwilling or unable to make all planned study visits.
  • Unwilling or unable to provide a recent biopsy or bone marrow prior to enrollment and during study.
    • Note: certain exceptions may be permitted allowing archival specimens prior to treatment or for subjects where specimen is not required for biomarker positive testing.
  • 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%.

 

 

 

Participating Mayo Clinic locations

Study statuses change often. Please contact the study team for the most up-to-date information regarding possible participation.

Mayo Clinic Location Status Contact

Scottsdale/Phoenix, Ariz.

Mayo Clinic principal investigator

Mahesh Seetharam, M.D.

Open for enrollment

Contact information:

Cancer Center Clinical Trials Referral Office

(855) 776-0015

-

Rochester, Minn.

Mayo Clinic principal investigator

Grzegorz Nowakowski, M.D.

Open for enrollment

Contact information:

Cancer Center Clinical Trials Referral Office

(855) 776-0015

-

Jacksonville, Fla.

Mayo Clinic principal investigator

Han Tun, M.D.

Open for enrollment

Contact information:

Cancer Center Clinical Trials Referral Office

(855) 776-0015

-

More information

Publications

Publications are currently not available

Study Results Summary

Not yet available

Supplemental Study Information

Not yet available

Additional contact information

Cancer-related trials contact form

Phone: 855-776-0015 (toll-free)

International patient clinical studies questions