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A Study to Evaluate the Effectiveness and Tolerability of a Second Maintenance Treatment in Participants With Ovarian Cancer, Who Have Previously Received Polyadenosine 5'Diphosphoribose [Poly (ADP Ribose)] Polymerase Inhibitor (PARPi) Treatment.

NCT04239014

Description:

To investigate the effectiveness and tolerability of a second maintenance treatment in participants with platinum-sensitivity relapsed (PSR) epithelial ovarian cancer, who have previously received PARPi maintenance treatment and who have benefit (complete response [CR] or partial response [PR]) or stable disease (SD) from further platinum based chemotherapy.

Related Conditions:
  • Fallopian Tube Carcinoma
  • Ovarian Carcinoma
  • Primary Peritoneal Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: A Study to Evaluate the Effectiveness and Tolerability of a Second Maintenance Treatment in Participants With Ovarian Cancer, Who Have Previously Received Polyadenosine 5'Diphosphoribose [Poly (ADP Ribose)] Polymerase Inhibitor (PARPi) Treatment.
  • Official Title: A Phase 2 Randomized, Multi-Centre Study to Investigate the Efficacy and Tolerability of a Second Maintenance Treatment in Patients With Platinum Sensitive Relapsed Epithelial Ovarian Cancer, Who Have Previously Received PARP Inhibitor Maintenance Treatment

Clinical Trial IDs

  • ORG STUDY ID: D6018C00004
  • NCT ID: NCT04239014

Conditions

  • Ovarian Cancer

Interventions

DrugSynonymsArms
OlaparibAZD2281Arm 1 (ceralasertib+olaparib)
CeralasertibAZD6738Arm 1 (ceralasertib+olaparib)
Placebo to match olaparibArm 3 (placebo)

Purpose

To investigate the effectiveness and tolerability of a second maintenance treatment in participants with platinum-sensitivity relapsed (PSR) epithelial ovarian cancer, who have previously received PARPi maintenance treatment and who have benefit (complete response [CR] or partial response [PR]) or stable disease (SD) from further platinum based chemotherapy.

Detailed Description

      This is a Phase II, randomised, multicentre study to investigate the efficacy and
      tolerability of a second maintenance treatment in participants with PSR epithelial ovarian
      cancer, who have previously received PARPi maintenance treatment and who have benefit (CR or
      PR) or SD from further platinum based chemotherapy.

      Participants will be recruited globally from approximately 120 study sites in the USA,
      Canada, Middle East and Europe.

      Approximately 192 participants fulfilling all of the inclusion criteria and none of the
      exclusion criteria will be randomised in a 1:1:1 ratio to the following 3 treatment arms (64
      participants per arm):

        -  Arm 1 (ceralasertib+olaparib): Ceralasertib 160 mg once daily (QD) orally or per os (PO)
           on Days 1 to 7 plus olaparib 300 mg twice daily (BD) PO continuous (28 day cycle)

        -  Arm 2 (olaparib monotherapy): Olaparib 300 mg BD PO daily continuous

        -  Arm 3 (placebo): Placebo to match olaparib BD PO daily continuous

      The olaparib and placebo arms will be double blinded, whereas the ceralasertib+olaparib arm
      will be open label. It is expected that approximately 320 participants will be screened.
    

Trial Arms

NameTypeDescriptionInterventions
Arm 1 (ceralasertib+olaparib)ExperimentalParticipants received ceralasertib 160 mg QD PO on Days 1 to 7 plus olaparib 300 mg BD PO continuous (28 day cycle).
  • Olaparib
  • Ceralasertib
Arm 2 (olaparib monotherapy)ExperimentalOlaparib 300 mg BD PO daily continuous.
  • Olaparib
Arm 3 (placebo)ExperimentalPlacebo to match olaparib BD PO daily continuous.
  • Placebo to match olaparib

Eligibility Criteria

        Inclusion Criteria:

          -  Capable of providing signed informed consent, which includes compliance with the
             requirements and restrictions listed in the ICF and in the Clinical Study Protocol
             (CSP).

          -  Provision of signed and dated, written ICF prior to any mandatory study specific
             procedures, sampling, and analyses.

          -  Female ≥18 years of age at the time of signing the ICF.

          -  Eastern Cooperative Oncology Group performance status 0 to 1 within 28 days of
             randomization.

          -  Participants with relapsed histologically confirmed diagnosis of high grade epithelial
             ovarian cancer (including primary peritoneal and/or fallopian tube cancer), with
             disease relapse on or after completion of PARPi maintenance therapy and who have not
             received any intervening systemic treatment since discontinuation of PARPi (this
             excludes the platinum based chemotherapy received during Screening Part 1 of this
             study).

          -  A minimum of 6 months of prior PARPi treatment received in the maintenance setting for
             PSR ovarian cancer (a minimum of 12 months is required if the participant received
             PARPi maintenance following first line chemotherapy). If the prior PARPi used was
             olaparib then participants must have received treatment without significant toxicity
             or the need for a permanent dose reduction.

          -  Disease relapse in the second line (first relapse) or third line (second relapse)
             setting.

          -  Able to provide and consent to the collection of a contemporaneous tumor tissue biopsy
             and blood sample.

          -  Able to provide a Formalin Fixed Paraffin Embedded archival tumour tissue block from
             the time of primary tumour diagnosis (taken ideally prior to receiving any systemic
             treatment, and definitely prior to first PARPi treatment) for prospective Breast
             cancer susceptibility gene (BRCA) status testing. If tumour blocks are unavailable,
             tissue sections are acceptable with a minimum requirement of at least 20 unstained
             sections on uncharged slides without cover slips. Fine needle aspirates are not
             acceptable.

          -  Where the patient has previously been tested for germline or somatic BRCA alterations
             using a verified and well-validated test in line with local regulations, performed in
             a locally accredited laboratory (eg, College of American Pathologists/Clinical
             Laboratory Improvement Amendments laboratory, where available), and signed consent to
             provide a copy of the BRCA report.

          -  Platinum-sensitive disease at the time of disease relapse, i.e, platinum-treatment
             free survival of greater than 6 months as defined by the Gynecological Cancer
             Intergroup (Wilson et al 2017).

          -  For the platinum-based chemotherapy course received following pre screening (Part 1)
             and prior to entering the main screening (Part 2).

          -  Any prior palliative radiation must have been completed at least 7 days prior to the
             start of study drugs, and participants must have recovered from any acute adverse
             effects prior to the start of study treatment.

          -  Normal organ and bone marrow function measured within 28 days prior to randomization.

          -  Participant is willing and able to comply with the CSP for the duration of the study
             including undergoing treatment and scheduled visits and examinations.

          -  Participants must have a life expectancy of ≥16 weeks.

          -  Participants must be able to swallow tablets whole.

          -  For inclusion in the optional (deoxyribonucleic acid) genetics research, study
             participants must fulfil the following criterion:

        Provide informed consent for the genetic sampling and analyses. If a participant declines
        to participate in the genetics research, there will be no penalty or loss of benefit to the
        participant. A participant who declines genetics research participation will not be
        excluded from any other aspect of the main study.

          -  Participant's body weight must be >30 kg.

          -  Postmenopausal or evidence of non-childbearing status for women of childbearing
             potential.

          -  Women of childbearing potential and their partners, who are sexually active, must
             agree to the use of 2 highly effective forms of contraception in combination from the
             signing of the informed consent (Screening Part 1), throughout the period of taking
             study treatment and for at least 6 months after the last dose of study drug(s).

        Exclusion Criteria:

          -  Participants who have had drainage of their ascites during the final 2 cycles of their
             last chemotherapy regimen or during the period between completion of chemotherapy and
             first dose of study treatment.

          -  Participants with current signs or symptoms of bowel obstruction, including
             sub-occlusive disease, related to underlying disease.

          -  History of leptomeningeal carcinomatosis.

          -  Participants with symptomatic uncontrolled brain metastases.

               1. A scan to confirm the absence of brain metastases is not required.

               2. Participants whose brain metastases have been treated may participate provided
                  they show radiographic stability. In addition, any neurologic symptoms that
                  developed either as a result of the brain metastases or their treatment must have
                  resolved or be stable (Common Terminology Criteria for Adverse Events [CTCAE]
                  Grade <2) either, without the use of steroids, or are stable on a steroid dose of
                  ≤10 mg/day of prednisone or its equivalent and stable on anti convulsants if
                  required for at least 14 days prior to the start of treatment.

               3. Participants with spinal cord compression are not eligible unless considered to
                  have received definitive treatment for this and have evidence of clinically SD
                  for >28 days and have not received steroid treatment for at least 14 days prior
                  to the start of study treatment.

          -  History of another primary malignancy except for:

               1. Malignancy treated with curative intent and with no known active disease ≥5 years
                  before the first dose of IP and of low potential risk for recurrence;

               2. Adequately treated non-melanoma skin cancer or lentigo maligna without evidence
                  of disease;

               3. Adequately treated carcinoma in situ without evidence of disease.

          -  Major surgical procedures (as defined by the investigator) ≤28 days of beginning study
             treatment, or minor surgical procedures ≤7 days. No waiting period required following
             port a cath or other central venous access placement.

          -  Persistent toxicities (≥CTCAE Grade 2) caused by previous cancer therapy, excluding
             alopecia and CTCAE Grade 2 peripheral neuropathy. Note: participants with signs of
             ongoing complications from radiation therapy are not eligible for this study.

          -  Participants with myelodysplastic syndrome (MDS) /acute myeloid leukemia (AML) or with
             features suggestive of MDS/AML.

          -  Resting electrocardiogram indicating uncontrolled, potentially reversible cardiac
             conditions, as judged by the investigator, or participants with congenital long QT
             syndrome.

          -  Known allergy or hypersensitivity to any of the study drugs or any of the study drug
             excipients.

          -  History of allogeneic organ transplantation including previous allogeneic bone marrow
             transplant or double umbilical cord blood transplantation.

          -  History of active primary immunodeficiency.

          -  Active infection including tuberculosis (TB), hepatitis B (known positive hepatitis B
             virus [HBV] surface antigen [HBsAg] result), hepatitis C (HCV), or human
             immunodeficiency virus (HIV) (positive HIV 1/2 antibodies). Participants with a past
             or resolved HBV infection are eligible. Participants positive for HCV antibody are
             eligible only if polymerase chain reaction is negative for HCV ribonucleic acid.

          -  Uncontrolled intercurrent illness, including but not limited to, ongoing or active
             infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable
             angina pectoris, uncontrolled cardiac arrhythmia, active interstitial lung disease,
             serious chronic gastrointestinal conditions associated with diarrhea, or psychiatric
             illness/social situations.

          -  Current dependency on total parenteral nutrition or intravenous (iv) fluid hydration.

          -  Whole blood transfusions in the last 120 days prior to entry to the study.

          -  Cytotoxic chemotherapy, hormonal or non hormonal targeted therapy within 21 days of
             Cycle 1, Day 1 is not permitted. The participant can receive a stable dose of
             bisphosphonates or denosumab for bone metastases, before and during the study as long
             as these were started at least 5 days prior to study treatment.

          -  Participation in another clinical study with an IP during the chemotherapy course
             immediately prior to randomisation or during the course of the study.

          -  Previous treatment with ceralasertib or other ataxia telangiectasia and Rad3-related
             protein, Checkpoint kinase 1 or deoxyribonucleic acid damage response inhibitor
             (excluding PARPi).

          -  Exposure to a small molecule IP within 30 days or 5 half-lives (whichever is longer)
             prior to randomization. The minimum washout period for immunotherapy and bevacizumab
             shall be 42 days.

          -  Receipt of live attenuated vaccine within 30 days prior to the first dose of study
             treatment.

          -  Concomitant use of known strong cytochrome P450 (CYP) 3A inhibitors or moderate CYP3A
             inhibitors. The required washout period prior to starting study treatment is 2 weeks.

          -  Concomitant use of known strong CYP3A inducers or moderate CYP3A inducers. The
             required washout period prior to starting study treatment is 5 weeks for enzalutamide
             or phenobarbital and 3 weeks for other agents.

          -  Involvement in the planning and/or conduct of the study (applies to Sponsor staff
             and/or staff at the study site).

          -  Previous randomization in the present study.

          -  Judgment by the investigator that the participant should not participate in the study
             if the participant is unlikely to comply with study procedures, restrictions and
             requirements.

          -  Pregnant or lactating women.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Female
Healthy Volunteers:No

Primary Outcome Measures

Measure:Progression free survival (PFS)
Time Frame:To assess from the time of randomization until the date of objective disease progression or death (by any cause in the absence of progression) or approximately up to 2.5 years.
Safety Issue:
Description:To assess the efficacy of maintenance olaparib monotherapy and ceralasertib+olaparib combination therapy compared with placebo.

Secondary Outcome Measures

Measure:Overall survival (OS)
Time Frame:To assess every 8 weeks (±7 days) for first 72 weeks following objective disease progression or treatment discontinuation and then every 12 weeks, up to approximately 2.5 years.
Safety Issue:
Description:To further assess the efficacy of maintenance olaparib monotherapy and ceralasertib+olaparib combination therapy compared with placebo; and to assess the efficacy of maintenance ceralasertib+olaparib combination therapy compared with olaparib monotherapy.
Measure:Time to second progression
Time Frame:To assess every 8 weeks (±7 days) for first 72 weeks following objective disease progression or treatment discontinuation and then every 12 weeks, up to approximately 2.5 years.
Safety Issue:
Description:To further assess the efficacy of maintenance olaparib monotherapy and ceralasertib+olaparib combination therapy compared with placebo; and to assess the efficacy of maintenance ceralasertib+olaparib combination therapy compared with olaparib monotherapy. A participant's second progression status is defined according to the local standard clinical practice and may involve any of; investigator assessment of radiological progression, cancer antigen 125 (CA 125) progression, symptomatic progression or death.
Measure:Objective response rate
Time Frame:At baseline, every 8 weeks for first 72 weeks, then every 12 weeks after randomization until objective disease progression or approximately up to 2.5 years.
Safety Issue:
Description:To further assess the efficacy of maintenance olaparib monotherapy and ceralasertib+olaparib combination therapy compared with placebo; and to assess the efficacy of maintenance ceralasertib+olaparib combination therapy compared with olaparib monotherapy.
Measure:Duration of response
Time Frame:At baseline, every 8 weeks for first 72 weeks, then every 12 weeks after randomization until objective disease progression or approximately up to 2.5 years.
Safety Issue:
Description:To further assess the efficacy of maintenance olaparib monotherapy and ceralasertib+olaparib combination therapy compared with placebo; and to assess the efficacy of maintenance ceralasertib+olaparib combination therapy compared with olaparib monotherapy.
Measure:Percentage change in tumour size
Time Frame:At baseline, every 8 weeks for first 72 weeks, then every 12 weeks after randomization until objective disease progression or approximately up to 2.5 years.
Safety Issue:
Description:To further assess the efficacy of maintenance olaparib monotherapy and ceralasertib+olaparib combination therapy compared with placebo.
Measure:Plasma concentration data for olaparib and ceralasertib
Time Frame:At cycle 1 Day 1 and Day 7
Safety Issue:
Description:To evaluate the pharmacokinetic (PK) exposure of ceralasertib+olaparib combination therapy.
Measure:Change from baseline in European Organisation for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC-QLQ) C30
Time Frame:At Cycle1 Day 1, every 4 weeks from Cycle 1 Day 1 until treatment discontinuation, and follow-up 30 days after last dose of study medication.
Safety Issue:
Description:To assess the impact of maintenance olaparib monotherapy and ceralasertib+olaparib combination therapy compared with placebo on participants' symptoms, functioning, and Health-related quality of life (HRQoL). Questions are grouped into functional scales, symptom scales, a global health status / quality of life (QoL) scale, assessing additional symptoms commonly reported by cancer participants, and the financial impact of the disease. All but 2 questions are rated on a 4 point verbal rating scale: "Not at all," "A little," "Quite a bit," and "Very much." The 2 questions concerning global health status and QoL have 7 point scales with ratings ranging from "Very poor" to "Excellent." For each of the 15 domains, final scores are transformed such that they range from 0 to 100, where higher scores indicate better functioning, better QoL, or worse symptoms.
Measure:Change from baseline in EORTC-QLQ-OV28
Time Frame:At Cycle1 Day 1, every 4 weeks from Cycle 1 Day 1 until treatment discontinuation, and follow-up 30 days after last dose of study medication.
Safety Issue:
Description:To assess the impact of maintenance olaparib monotherapy and ceralasertib+olaparib combination therapy compared with placebo on participants' symptoms, functioning, and HRQoL It consists of 28 items assessing abdominal/gastrointestinal symptoms (6 items), peripheral neuropathy (2 items), other chemotherapy side effects (5 items), hormonal symptoms (2 items), body image (2 items), attitudes to disease/treatment (3 items), sexuality (4 items) and 4 other single items. All questions are rated on a 4 point verbal rating scale: "Not at all," "A little," "Quite a bit," and "Very much." Final scores are transformed such that they range from 0 to 100, where higher scores indicate greater functioning, greater QoL, or greater level of symptoms.
Measure:Time to earliest progression by RECIST 1.1 or CA-125 or death
Time Frame:At baseline, every 8 weeks for first 72 weeks, then every 12 weeks after randomization until objective disease progression or approximately up to 2.5 years.
Safety Issue:
Description:Time to progression by RECIST 1.1 or CA-125 progression or death is defined as the time from randomisation to the earlier date of RECIST 1.1 or CA-125 progression or death by any cause.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:AstraZeneca

Trial Keywords

  • Platinum Sensitive Relapsed Epithelial Ovarian Cancer
  • Polyadenosine 5'diphosphoribose (poly [ADP ribose]) polymerase inhibitor (PARPi)

Last Updated

September 4, 2020