Cirtuvivint plus Olaparib for BRCA/HRD-positive, platinum-resistant ovarian, fallopian tube, or primary peritoneal cancer

Phase I Evaluation of Combination CLK/DYRK (Cirtuvivint) Inhibition With PARP Inhibition (Olaparib) in BRCA/HRD Platinum Resistant Ovarian Cancer

We will test whether adding cirtuvivint to daily olaparib is safe and tolerable for women with BRCA- or HRD-positive, platinum-resistant high-grade ovarian, fallopian tube, or primary peritoneal cancer.

Quick facts

• Phase: Phase 1
• Study type: Interventional
• Enrollment: 50 (estimated)
• Ages: 18 Years and up
• Sex: Female
• Sponsor: University of Colorado, Denver (Academic / other)
• Drugs / interventions: Bevacizumab, chemotherapy, radiation
• Locations: 2 sites (Aurora, Colorado and 1 other locations)
• Trial ID: NCT06856499 on ClinicalTrials.gov

What this trial studies

This is a non-comparative Phase 1 trial testing two oral cirtuvivint dosing schedules combined with continuous twice-daily olaparib in 28-day cycles to determine safety and the recommended Phase 2 dose. Patients with germline or somatic BRCA mutations or homologous recombination deficiency (HRD) who have platinum-resistant high-grade serous or endometrioid ovarian, fallopian tube, or primary peritoneal cancer and measurable disease will be enrolled. Cohorts alternate enrollment between cirtuvivint given 5 days on/2 days off and 2 days on/5 days off while olaparib is given at 300 mg twice daily, and clinic visits are frequent early then occur every 28 days after the first two months. Safety monitoring includes physical exams, blood tests, vital signs, and imaging with limits of no more than three prior systemic therapy lines for eligibility.

Who should consider this trial

Good fit: Women 18 or older with high-grade serous or endometrioid ovarian, fallopian tube, or primary peritoneal cancer that is platinum-resistant, BRCA-mutated or HRD-positive, with ECOG 0–2, measurable disease, and no more than three prior systemic therapy lines are ideal candidates.

Not a fit: Patients who are BRCA/HRD-negative, have platinum-sensitive disease, have received more than three prior systemic therapies, or have poor performance status are unlikely to benefit from this trial.

Why it matters

Potential benefit: If successful, the combination could offer a new treatment option that helps overcome PARP resistance and extend disease control for BRCA/HRD-positive, platinum-resistant patients.

How similar studies have performed: PARP inhibitors like olaparib are effective in BRCA/HRD ovarian cancer, but combining olaparib with cirtuvivint is a novel approach with limited prior clinical data.

Eligibility criteria

Inclusion Criteria:

1. Provision to sign and date the consent form.
2. Stated willingness to comply with all study procedures and be available for the duration of the study.
3. Woman aged ≥18 years of age
4. Patients must have an Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 1 or 2
5. Patients must have a confirmed diagnosis of high-grade serous or endometrioid epithelial ovarian cancer, primary peritoneal cancer, or fallopian tube cancer
6. Patients must have platinum-resistant disease defined as radiographic progression less than 6 months from last dose of most recent platinum therapy
7. Patients must have measurable disease by defined RECIST 1.1 criteria
8. Prior anticancer therapy:

   * Patients must have received at least one prior platinum-based chemotherapy regimen
   * Patients may not have received more than 3 prior lines of systemic therapy
   * Neoadjuvant +/- adjuvant therapies are considered 1 line of therapy
   * Maintenance therapy (eg, Bevacizumab, PARP inhibitors) will be considered part of preceding line of therapy (ie, not counted independently)
   * Therapy changed due to toxicity in the absence of progression will be considered part of the same line (ie, not counted independently)
   * Hormonal therapy will be counted as a separate line of therapy unless it was given as maintenance
   * Prior radiation is allowed and is not considered a line of treatment
9. Patients must have had testing for BRCA mutation (tumor or germline) and tumor HRD testing, and have been positive for one and/or the other.
10. Patients must have received a prior PARP inhibitor as either treatment or maintenance therapy
11. Patients must have adequate hematologic, liver, and kidney function as defined as:

    * Absolute neutrophil count (ANC) ≥ 1.5 x 109/L (1500/µL)
    * Platelet count ≥ 100 x 109/L (100,000 µL)
    * Hemoglobin ≥ 10.0 g/dL with no blood transfusion in the past 28 days
    * Serum creatinine ≤ 1.5 x upper limit of normal (ULN)
    * Patients must have creatinine clearance estimated of ≥51 mL/min using the Cockcroft-Gault equation or based on a 24 hour urine test
    * Aspartate aminotransferase (AST)(Serum Glutamic Oxaloacetic Transaminase (SGOT)) and alanine aminotransferase (ALT) (Serum Glutamic Pyruvate Transaminase (SGPT)) ≤ 2.5 x ULN unless liver metastases are present in which case they must be ≤ 5x ULN
    * Serum bilirubin ≤ 1.5 x ULN (patients with documented diagnosis of Gilbert syndrome are eligible if total bilirubin \< 3.0 x ULN)
    * Serum albumin ≥ 2 g/dL
12. Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial.
13. Ability to understand and the willingness to sign a written informed consent document. Participants with impaired decision-making capacity (IDMC) who have a legally-authorized representative (LAR) and/or family member available will also be eligible.

Exclusion Criteria:

1. Patients with clear cell, mucinous, sarcomatous, low grade/borderline, germ cell, or sex-cord stromal type ovarian tumor
2. Patients with platinum refractory disease as defined by those who have progressed during or within 4 weeks of receiving platinum-based therapy
3. Patients receiving any systemic chemotherapy or radiotherapy (except for palliative reasons) within 3 weeks prior to study treatment
4. Patients with myelodysplastic syndrome/acute myeloid leukemia or with features suggestive of myelodysplastic syndrome/acute myeloid leukemia.
5. Patients considered a poor medical risk due to a serious, uncontrolled medical disorder, non-malignant systemic disease or active, uncontrolled infection. Examples include, but are not limited to:

   * Uncontrolled major seizure disorder
   * Unstable spinal cord compression
   * Any psychiatric disorder that prohibits obtaining informed consent.
   * Any other concurrent infectious disease requiring IV antibiotics within 2 weeks prior to the first dose of therapy
6. Patients with clinically significant cardiac disease including, but not limited to, any of the following

   * Myocardial infarction ≤ 6 months prior to first dose
   * Uncontrolled ventricular arrhythmia, recent (within 3 months)
   * Superior vena cava syndrome
   * Unstable angina pectoris
   * Uncontrolled congestive heart failure (New York Heart Association \> class II)
   * Uncontrolled ≥ Grade 3 hypertension (per CTCAE)
   * Uncontrolled cardiac arrhythmias
7. Patients with a history of hemorrhagic or ischemic stroke within 6 months prior to enrollment
8. Patients with a history of cirrhotic liver disease (Child-Pugh Class B or C)
9. Persistent toxicities (\>/= Common Terminology Criteria for Adverse Event (CTCAE) grade 2) caused by previous cancer therapy, excluding alopecia or peripheral sensory neuropathy
10. Patients with duodenal stent or other GI disorder/defect that would interfere with absorption of oral medication

    o Includes patients unable to swallow orally administered medication and patients with gastrointestinal disorders likely to interfere with absorption of the study medication
11. Patients with known untreated or symptomatic central nervous system (CNS) metastases
12. Prior known hypersensitivity reaction to study drugs and/or any of their excipients
13. Minor or major surgical procedure within 2 weeks of starting study treatment and patients must have recovered from any effects of any major surgery.
14. Inability to comply with study and follow-up procedures
15. Patients deemed otherwise clinically unfit for clinical trial per investigators discretion.

Where this trial is running

Aurora, Colorado and 1 other locations

• CU Medicine Clinics — Aurora, Colorado, United States (Recruiting)
• Universtiy of Colorado Hospital — Aurora, Colorado, United States (Recruiting)

Study contacts

• Principal investigator: Bradley Corr — University of Colorado, Denver
• Study coordinator: Evamaria Kent Bravo, MS

Conditions Endometrioid Ovarian Cancer; Primary Peritoneal Cancer; Fallopian Tube Cancer