Clinical Trials /

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

NCT04633239

Description:

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.

Related Conditions:
  • Ovarian Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Testing the Addition of Abemaciclib to Olaparib for Women With Recurrent Ovarian Cancer
  • Official Title: A Phase 1/1b Dose Escalation Study of Abemaciclib and Olaparib for Recurrent Platinum-Resistant Ovarian Cancer

Clinical Trial IDs

  • ORG STUDY ID: NCI-2020-10084
  • SECONDARY ID: NCI-2020-10084
  • SECONDARY ID: 10422
  • SECONDARY ID: 10422
  • SECONDARY ID: UM1CA186689
  • NCT ID: NCT04633239

Conditions

  • Recurrent High Grade Ovarian Serous Adenocarcinoma
  • Recurrent Platinum-Resistant Ovarian Carcinoma

Interventions

DrugSynonymsArms
AbemaciclibLY-2835219, LY2835219, VerzenioTreatment (abemaciclib, olaparib)
OlaparibAZD 2281, AZD-2281, AZD2281, KU-0059436, Lynparza, PARP Inhibitor AZD2281Treatment (abemaciclib, olaparib)

Purpose

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.

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.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (abemaciclib, olaparib)ExperimentalPatients 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.
  • Abemaciclib
  • Olaparib

Eligibility 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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Female
Healthy Volunteers:No

Primary Outcome Measures

Measure:Recommended phase 2 dose (RP2D)
Time Frame:28 days (end of cycle 1)
Safety Issue:
Description: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

Measure:Overall response rate (ORR)
Time Frame:30 days after completion of study treatment
Safety Issue:
Description:ORR will be calculated using Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.
Measure:Duration of response (DoR)
Time Frame:30 days after completion of study treatment
Safety Issue:
Description: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).

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:National Cancer Institute (NCI)

Last Updated

May 24, 2021