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Testing the Addition of Abemaciclib to Olaparib for Women With Recurrent Ovarian Cancer

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ClinicalTrials.gov Identifier: NCT04633239
Recruitment Status : Recruiting
First Posted : November 18, 2020
Last Update Posted : September 16, 2021
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Brief Summary:
This phase I/Ib trial identifies the side effects and best dose of abemaciclib when given together with olaparib in treating patients with ovarian cancer that responds at first to treatment with drugs that contain the metal platinum but then comes back within a certain period (recurrent platinum-resistant). Abemaciclib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Olaparib is an inhibitor of PARP, an enzyme that helps repair deoxyribonucleic acid (DNA) when it becomes damaged. Blocking PARP may help keep tumor cells from repairing their damaged DNA, causing them to die. PARP inhibitors are a type of targeted therapy. Adding abemaciclib to olaparib may work better to treat recurrent platinum-resistant ovarian cancer.

Condition or disease Intervention/treatment Phase
Recurrent High Grade Ovarian Serous Adenocarcinoma Recurrent Platinum-Resistant Ovarian Carcinoma Drug: Abemaciclib Drug: Olaparib Phase 1

Detailed Description:

PRIMARY OBJECTIVE:

I. To assess the safety of abemaciclib plus olaparib in patients with platinum-resistant ovarian cancer by determining the maximum tolerated dose and recommended phase 2 dose.

SECONDARY OBJECTIVE:

I. To observe and record anti-tumor activity using overall response rate (ORR) and duration of response (DoR) with abemaciclib and olaparib, given in combination, in patients with platinum-resistant ovarian cancer.

EXPLORATORY OBJECTIVES:

I. To assess proof of mechanism (RB, phosphoRB, cleaved caspase 3, Ki67, geminin, gamma-H2AX, RAD51 nuclear foci, pNBS multiplex, Myc transcriptional targets ODC1 and LDHA, homologous recombination genes BRCA1, BRCA2, RAD51, serum thymidine kinase), plasma and tumor pharmacokinetics, and subgroups of response (immunohistochemistry [IHC] for Myc, cyclin E; next generation sequencing [NGS]/whole exome sequencing [WES] for DCAF, hormone receptor [HR] repair gene alterations, Myc, and CCNE1; ribonucleic acid sequencing [RNAseq] for Myc and CCNE1).

II. To contribute genetic analysis data from de-identified biospecimens to Genomic Data Commons (GDC), a well annotated cancer molecular and clinical data repository, for current and future research; specimens will be annotated with key clinical data, including presentation, diagnosis, staging, summary treatment, and if possible, outcome.

III. To bank formalin-fixed, paraffin-embedded (FFPE) tissue, blood (for cell-free DNA analysis), and nucleic acids obtained from patients at the Experimental Therapeutics Clinical Trials Network (ETCTN) Biorepository at Nationwide Children's Hospital.

OUTLINE: This is a dose-escalation study of abemaciclib.

Patients receive olaparib orally (PO) twice daily (BID) on days 1-28 and abemaciclib PO BID on days 8-28 of cycle 1 and days 1-28 of subsequent cycles. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 41 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 1/1b Dose Escalation Study of Abemaciclib and Olaparib for Recurrent Platinum-Resistant Ovarian Cancer
Actual Study Start Date : February 12, 2021
Estimated Primary Completion Date : November 12, 2022
Estimated Study Completion Date : November 12, 2022


Arm Intervention/treatment
Experimental: Treatment (abemaciclib, olaparib)
Patients receive olaparib PO BID on days 1-28 and abemaciclib PO BID on days 8-28 of cycle 1 and days 1-28 of subsequent cycles. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Drug: Abemaciclib
Given PO
Other Names:
  • LY-2835219
  • LY2835219
  • Verzenio

Drug: Olaparib
Given PO
Other Names:
  • AZD 2281
  • AZD-2281
  • AZD2281
  • KU-0059436
  • Lynparza
  • PARP Inhibitor AZD2281




Primary Outcome Measures :
  1. Recommended phase 2 dose (RP2D) [ Time Frame: 28 days (end of cycle 1) ]
    Safety and tolerability will be measured using Common Terminology Criteria for Adverse Events (CTCAE) version 5. The number of patients experiencing a dose limiting toxicity will be tabulated. The recommended phase 2 dose will be determined by the dose escalation phase using 3+3 design.


Secondary Outcome Measures :
  1. Overall response rate (ORR) [ Time Frame: 30 days after completion of study treatment ]
    ORR will be calculated using Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.

  2. Duration of response (DoR) [ Time Frame: 30 days after completion of study treatment ]
    DoR will be calculated using RECIST version 1.1. The duration of overall response is measured from the time measurement criteria are met for complete response (CR) or partial response (PR) (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented (taking as reference for progressive disease the smallest measurements recorded since the treatment started).


Other Outcome Measures:
  1. Biomarker analysis [ Time Frame: 30 days after completion of study treatment ]
    Will measure proof of mechanism (RB, phosphoRB, cleaved caspase 3, Ki67, geminin, gamma-H2AX, RAD51 nuclear foci, pNBS multiplex, Myc transcriptional targets ODC1 and LDHA, homologous recombination genes BRCA1, BRCA2, RAD51, serum thymidine kinase), plasma and tumor pharmacokinetics, and subgroups of response (immunohistochemistry [IHC] for Myc, cyclin E; next generation sequencing [NGS]/whole exome sequencing [WES] for DCAF, hormone receptor [HR] repair gene alterations, Myc, and CCNE1; ribonucleic acid sequencing [RNAseq] for Myc and CCNE1).



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Patients must have histologically confirmed recurrent platinum-resistant epithelial ovarian carcinoma (EOC) of any histology, as defined by progression within 6 months of the last dose of platinum-based chemotherapy. Both primary platinum resistant and acquired platinum resistant patients are allowed
  • High-grade serous histology is required (for the dose expansion cohort only)
  • Patients must have received 1-3 prior systemic therapies
  • Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)
  • Hemoglobin >= 10 g/dL (within 28 days prior to administration of study treatment)

    • Patients may receive erythrocyte transfusions to achieve this hemoglobin level at the discretion of the investigator. Initial treatment must not begin earlier than the day after the erythrocyte transfusion
  • Absolute neutrophil count >= 1,500/mcL (within 28 days prior to administration of study treatment)
  • Platelets >= 100,000/mcL (within 28 days prior to administration of study treatment)
  • Total bilirubin =< 1.5 x institutional upper limit of normal (ULN) (within 28 days prior to administration of study treatment)

    • Patients with Gilbert's syndrome with a total bilirubin =< 2.0 times ULN and direct bilirubin within normal limits are permitted
  • Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) / alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) =< 3 x institutional ULN, unless liver metastases are present in which case they must be =< 5 x ULN (within 28 days prior to administration of study treatment)
  • Patients must have creatinine clearance estimated of >= 51 mL/min using the Cockcroft-Gault equation or based on a 24-hour urine test (within 28 days prior to administration of study treatment)
  • Glomerular filtration rate (GFR) >= 60 mL/min/1.73 m^2 unless data exists supporting safe use at lower kidney function values, no lower than 30 mL/min/1.73 m^2 (within 28 days prior to administration of study treatment). Estimated GFR calculated using Cockcroft-Gault equation
  • Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial
  • For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated

    • Active hepatitis B virus (HBV) is defined by a known positive HBV surface antigen (HBsAg) result. Patients with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody and absence of HBsAg) are eligible
  • Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load.

    • Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV ribonucleic acid (RNA)
  • Patients with treated brain metastases are eligible if patient is stable for at least 4 weeks status post (s/p) radiation therapy and off corticosteroids, as ascertained by clinical examination and brain imaging (magnetic resonance imaging [MRI] or computed tomography [CT] scan) during the screening period
  • Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, patients should be class 2B or better
  • Postmenopausal or evidence of non-childbearing status, a negative urine or serum pregnancy test within 28 days of study treatment and confirmed prior to treatment on day 1. Postmenopausal is defined as:

    • Amenorrheic for 1 year or more following cessation of exogenous hormonal treatments
    • Luteinizing hormone (LH) and follicle stimulating hormone (FSH) levels in the postmenopausal range for women under 50
    • Radiation-induced oophorectomy with last menses > 1 year ago
    • Chemotherapy-induced menopause with > 1 year interval since last menses
    • Surgical sterilization (bilateral oophorectomy or hysterectomy)
  • The effects of abemaciclib and olaparib on the developing human fetus are unknown. For this reason and because CDK-and PARP-inhibiting agents are known to be teratogenic, women of child-bearing potential and their partners, who are sexually active, must agree to the use of one highly effective form of contraception and their partner must use a male condom prior to study entry, for the duration of study participation, and for 1 month after the last dose of study treatment. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately
  • For the dose expansion cohort, patients must have disease amenable to biopsy for correlative studies, specifically at least 1 tumor accessible and safe for biopsy on office exam or tumor that a radiologist deems is safe for biopsy in interventional radiology department based on imaging (dose expansion cohort only). For the dose escalation cohort, patients with evaluable disease are acceptable
  • For inclusion in i) the optional genetic research and ii) the optional biomarker research, patients must fulfill the following criteria:

    • Provision of informed consent for genetic research prior to collection of sample
    • Provision of informed consent for biomarker research prior to collection of sample
    • If a patient declines to participate in the optional exploratory genetic research or the optional biomarker research, there will be no penalty or loss of benefit to the patient. The patient will not be excluded from other aspects of the study
  • Patients may not have received prior CDK 4/6 inhibitors. Previous PARP inhibitor use is allowed in front-line treatment but not for recurrent disease
  • Patients who received chemotherapy must have recovered (Common Terminology Criteria for Adverse Events [CTCAE] grade =< 1) from the acute effects of chemotherapy except for residual alopecia or grade 2 peripheral neuropathy prior to randomization. A washout period of at least 21 days is required between last chemotherapy dose and randomization (provided the patient did not receive radiotherapy)
  • Patients who received radiotherapy must have completed and fully recovered from the acute effects of radiotherapy. A washout period of at least 28 days is required between end of radiotherapy and randomization
  • For agents other than chemotherapy, a 4 week washout period is required. Previous bevacizumab use is allowed
  • 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:

  • Patients who are receiving any other investigational agents
  • History of allergic reaction or hypersensitivity attributed to compounds of similar chemical or biologic composition to abemaciclib, olaparib or any of the excipients of these products
  • Concomitant use of known strong CYP3A inhibitors (e.g. itraconazole, telithromycin, clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, indinavir, saquinavir, nelfinavir, boceprevir, telaprevir) or moderate CYP3A inhibitors (e.g. ciprofloxacin, erythromycin, diltiazem, fluconazole, verapamil). The required washout period prior to starting study treatment is 2 weeks. Because the lists of these agents are constantly changing, it is important to regularly consult a frequently-updated medical reference. As part of the enrollment/informed consent procedures, the patient will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the patient is considering a new over-the-counter medicine or herbal product
  • Patients with psychiatric illness/social situations that would limit compliance with study requirements
  • Pregnant women are excluded from this study because abemaciclib is a CDK-inhibiting agent and olaparib is a PARP inhibiting agent with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with abemaciclib and olaparib, breastfeeding should be discontinued if the mother is treated with abemaciclib and olaparib
  • Other malignancy unless curatively treated with no evidence of disease for >= 5 years except: adequately treated non-melanoma skin cancer, curatively treated in situ cancer of the cervix, ductal carcinoma in situ (DCIS), stage 1, grade 1 endometrial carcinoma
  • Resting electrocardiogram (ECG) indicating uncontrolled, potentially reversible cardiac conditions, as judged by the investigator (e.g., unstable ischemia, uncontrolled symptomatic arrhythmia, congestive heart failure, corrected QT [QTcF] prolongation > 500 ms, electrolyte disturbances, ventricular tachycardia and ventricular fibrillation), or sudden cardiac arrest, etc.), or patients with congenital long QT syndrome
  • Patients with myelodysplastic syndrome/acute myeloid leukemia or with features suggestive of myelodysplastic syndrome/acute myeloid leukemia (MDS/AML)
  • Patients considered a poor medical risk due to a serious, uncontrolled medical disorder, non-malignant systemic disease or active, uncontrolled infection that, in the judgment of the investigator, would preclude participation in this study. Examples include, but are not limited to, uncontrolled ventricular arrhythmia, recent (within 3 months) myocardial infarction, uncontrolled major seizure disorder, unstable spinal cord compression, superior vena cava syndrome, extensive interstitial bilateral lung disease on high resolution computed tomography (HRCT) scan, severe dyspnea at rest or requiring oxygen therapy, severe renal impairment [e.g. estimated creatinine clearance < 30 ml/min], history of major surgical resection involving the stomach or small bowel, or preexisting Crohn's disease or ulcerative colitis or a preexisting chronic condition resulting in baseline grade 2 or higher diarrhea)
  • Patients unable to swallow orally administered medication and patients with gastrointestinal disorders likely to interfere with absorption of the study medication
  • Major surgery within 2 weeks of starting study treatment and patients must have recovered from any effects of any major surgery
  • Previous allogenic bone marrow transplant or double umbilical cord blood transplantation (dUCBT)
  • Patients with an active systemic fungal infection

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): NCT04633239


Locations
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United States, Arizona
Mayo Clinic Hospital in Arizona Recruiting
Phoenix, Arizona, United States, 85054
Contact: Site Public Contact    855-776-0015      
Principal Investigator: Andrea E. Wahner Hendrickson         
United States, Florida
Mayo Clinic in Florida Recruiting
Jacksonville, Florida, United States, 32224-9980
Contact: Site Public Contact    855-776-0015      
Principal Investigator: Andrea E. Wahner Hendrickson         
United States, Illinois
Northwestern University Recruiting
Chicago, Illinois, United States, 60611
Contact: Site Public Contact    312-695-1301    cancer@northwestern.edu   
Principal Investigator: Emma Barber         
United States, Minnesota
Mayo Clinic in Rochester Recruiting
Rochester, Minnesota, United States, 55905
Contact: Site Public Contact    855-776-0015      
Principal Investigator: Andrea E. Wahner Hendrickson         
United States, Ohio
Ohio State University Comprehensive Cancer Center Recruiting
Columbus, Ohio, United States, 43210
Contact: Site Public Contact    800-293-5066    Jamesline@osumc.edu   
Principal Investigator: David M. O'Malley         
United States, Oklahoma
University of Oklahoma Health Sciences Center Recruiting
Oklahoma City, Oklahoma, United States, 73104
Contact: Site Public Contact    405-271-8777    ou-clinical-trials@ouhsc.edu   
Principal Investigator: Kathleen N. Moore         
United States, Pennsylvania
Thomas Jefferson University Hospital Recruiting
Philadelphia, Pennsylvania, United States, 19107
Contact: Site Public Contact    215-600-9151    ONCTrialNow@jefferson.edu   
Principal Investigator: Lindsey E. Minion         
United States, Virginia
University of Virginia Cancer Center Recruiting
Charlottesville, Virginia, United States, 22908
Contact: Site Public Contact    434-243-6303    uvacancertrials@hscmail.mcc.virginia.edu   
Principal Investigator: Linda R. Duska         
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Camille Gunderson Yale University Cancer Center LAO
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Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT04633239    
Other Study ID Numbers: NCI-2020-10084
NCI-2020-10084 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
10422 ( Other Identifier: Yale University Cancer Center LAO )
10422 ( Other Identifier: CTEP )
UM1CA186689 ( U.S. NIH Grant/Contract )
First Posted: November 18, 2020    Key Record Dates
Last Update Posted: September 16, 2021
Last Verified: September 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: NCI is committed to sharing data in accordance with NIH policy. For more details on how clinical trial data is shared, access the link to the NIH data sharing policy page.
URL: https://grants.nih.gov/policy/sharing.htm

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Cystadenocarcinoma, Serous
Adenocarcinoma
Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Cystadenocarcinoma
Neoplasms, Cystic, Mucinous, and Serous
Olaparib
Poly(ADP-ribose) Polymerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents