Clinical trial NCT04239014: 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
Study type: INTERVENTIONAL
Overall status: WITHDRAWN
Phase: PHASE2
Conditions: Ovarian Cancer
Keywords: Platinum Sensitive Relapsed Epithelial Ovarian Cancer
Polyadenosine 5'diphosphoribose (poly [ADP ribose]) polymerase inhibitor (PARPi)
Lead sponsor: AstraZeneca
Sponsor class: INDUSTRY
Collaborators: name: Parexel
First posted: 2020-01-23
Enrollment: 0
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 130
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

The study achieved First Subject In date, but enrollment equals 0 as 7 participants have signed the Informed Consent Form (ICF) and were later screen failed.

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.

Primary outcomes:
measure: Progression free survival (PFS)
timeFrame: 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.
Secondary outcomes:
measure: Overall survival (OS)
timeFrame: 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.
measure: Time to second progression
timeFrame: 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.
measure: Objective response rate
timeFrame: 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.
measure: Duration of response
timeFrame: 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.
measure: Percentage change in tumour size
timeFrame: 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.
measure: Plasma concentration data for olaparib and ceralasertib
timeFrame: At cycle 1 Day 1 and Day 7
measure: Change from baseline in European Organisation for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC-QLQ) C30
timeFrame: 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.
measure: Change from baseline in EORTC-QLQ-OV28
timeFrame: 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.
measure: Time to earliest progression by RECIST 1.1 or CA-125 or death
timeFrame: 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.
Other outcomes:
measure: Number of participants with adverse events (AEs)
timeFrame: From Cycle 1 Day 1 to follow-up 30 days after the last dose of study medication.
measure: Number of participants with abnormal physical examination
timeFrame: From Cycle 1 Day 1 to follow-up 30 days after the last dose of study medication.
measure: Number of participants with abnormal Eastern Cooperative Oncology Group (ECOG) performance status (PS)
timeFrame: From Cycle 1 Day 1 to follow-up 30 days after the last dose of study medication.
measure: Number participants with abnormal systolic and diastolic blood pressure
timeFrame: From Cycle 1 Day 1 to follow-up 30 days after the last dose of study medication.
measure: Number of participants with abnormal pulse
timeFrame: From Cycle 1 Day 1 to follow-up 30 days after the last dose of study medication.
measure: Number of participants with abnormal body temperature
timeFrame: From Cycle 1 Day 1 to follow-up 30 days after the last dose of study medication.
measure: Number of participants with abnormal electrocardiogram
timeFrame: From Cycle 1 Day 1 to follow-up 30 days after the last dose of study medication.
measure: Number of participants with abnormal hemoglobin (Hb)
timeFrame: From Cycle 1 Day 1 to follow-up 30 days after the last dose of study medication.
measure: Number of participants with abnormal leukocyte count
timeFrame: From Cycle 1 Day 1 to follow-up 30 days after the last dose of study medication.
measure: Number of participants with abnormal absolute neutrophil count (ANC)
timeFrame: From Cycle 1 Day 1 to follow-up 30 days after the last dose of study medication.
measure: Number of participants with abnormal absolute lymphocyte count
timeFrame: From Cycle 1 Day 1 to follow-up 30 days after the last dose of study medication.
measure: Number of participants with abnormal platelet count
timeFrame: From Cycle 1 Day 1 to follow-up 30 days after the last dose of study medication.
measure: Number of participants with abnormal mean cell volume
timeFrame: From Cycle 1 Day 1 to follow-up 30 days after the last dose of study medication.
measure: Number of participants with abnormal serum creatinine
timeFrame: From Cycle 1 Day 1 to follow-up 30 days after the last dose of study medication.
measure: Number of participants with abnormal serum total bilirubin
timeFrame: From Cycle 1 Day 1 to follow-up 30 days after the last dose of study medication.
measure: Number of participants with abnormal serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase
timeFrame: From Cycle 1 Day 1 to follow-up 30 days after the last dose of study medication.
measure: Number of participants with abnormal serum potassium, calcium and sodium
timeFrame: From Cycle 1 Day 1 to follow-up 30 days after the last dose of study medication.
measure: Number of participants with abnormal plasma glucose
timeFrame: From Cycle 1 Day 1 to follow-up 30 days after the last dose of study medication.
measure: Number of participants with abnormal serum lactate dehydrogenase
timeFrame: From Cycle 1 Day 1 to follow-up 30 days after the last dose of study medication.
measure: Number of participants with abnormal creatinine clearance
timeFrame: From Cycle 1 Day 1 to follow-up 30 days after the last dose of study medication.
measure: Number of participants with abnormal serum urea or blood urea nitrogen
timeFrame: From Cycle 1 Day 1 to follow-up 30 days after the last dose of study medication.
measure: Number of participants with abnormal plasma total protein
timeFrame: From Cycle 1 Day 1 to follow-up 30 days after the last dose of study medication.
measure: Number of participants with abnormal urine Hb/erythrocytes/blood
timeFrame: From Cycle 1 Day 1 to follow-up 30 days after the last dose of study medication.
measure: Number of participants with abnormal urine protein/albumin
timeFrame: From Cycle 1 Day 1 to follow-up 30 days after the last dose of study medication.
measure: Number of participants with abnormal urine glucose
timeFrame: From Cycle 1 Day 1 to follow-up 30 days after the last dose of study medication.
measure: Number of participants with abnormal urine ketones
timeFrame: From Cycle 1 Day 1 to follow-up 30 days after the last dose of study medication.
measure: Number of participants with abnormal urine pH
timeFrame: From Cycle 1 Day 1 to follow-up 30 days after the last dose of study medication.
measure: Number of participants with abnormal specific gravity
timeFrame: From Cycle 1 Day 1 to follow-up 30 days after the last dose of study medication.
measure: Number of participants with abnormal urine bilirubin
timeFrame: From Cycle 1 Day 1 to follow-up 30 days after the last dose of study medication.
measure: European quality of life 5 dimensions, 5 level
timeFrame: From Cycle 1 Day 1 to follow-up 30 days after the last dose of study medication.
measure: Patient Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE)
timeFrame: From Cycle 1 Day 1 to follow-up 30 days after the last dose of study medication.
measure: Patient global impression of severity
timeFrame: From Cycle 1 Day 1 to follow-up 30 days after the last dose of study medication.
measure: Patient global impression of change
timeFrame: From Cycle 1 Day 1 to follow-up 30 days after the last dose of study medication.
measure: Patient global impression-treatment tolerability
timeFrame: From Cycle 1 Day 1 to follow-up 30 days after the last dose of study medication.
measure: Patient global impression-benefit risk
timeFrame: From Cycle 1 Day 1 to 12 weeks and 16 weeks of study medication.
Locations:
city: Anchorage
country: United States
facility: Research Site
state: Alaska
city: La Jolla
country: United States
facility: Research Site
state: California
city: Long Beach
country: United States
facility: Research Site
state: California
city: Los Angeles
country: United States
facility: Research Site
state: California
city: West Hollywood
country: United States
facility: Research Site
state: California
city: Hartford
country: United States
facility: Research Site
state: Connecticut
city: Tampa
country: United States
facility: Research Site
state: Florida
city: Atlanta
country: United States
facility: Research Site
state: Georgia
city: Louisville
country: United States
facility: Research Site
state: Kentucky
city: Covington
country: United States
facility: Research Site
state: Louisiana
city: Florham Park
country: United States
facility: Research Site
state: New Jersey
city: Teaneck
country: United States
facility: Research Site
state: New Jersey
city: Cleveland
country: United States
facility: Research Site
state: Ohio
city: Oklahoma City
country: United States
facility: Research Site
state: Oklahoma
city: Tulsa
country: United States
facility: Research Site
state: Oklahoma
city: Portland
country: United States
facility: Research Site
state: Oregon
city: Abington
country: United States
facility: Research Site
state: Pennsylvania
city: Philadelphia
country: United States
facility: Research Site
state: Pennsylvania
city: Sioux Falls
country: United States
facility: Research Site
state: South Dakota
city: Sioux Falls
country: United States
facility: Research Site
state: South Dakota
city: Houston
country: United States
facility: Research Site
state: Texas
city: Seattle
country: United States
facility: Research Site
state: Washington
city: Toronto
country: Canada
facility: Research Site
state: Ontario
city: Montreal
country: Canada
facility: Research Site
state: Quebec
city: Napoli
country: Italy
facility: Research Site
city: Barcelona
country: Spain
facility: Research Site
Study officials:
affiliation: Princess Margaret Cancer Centre, UHN and Mt. Sinai Health System
name: Dr Amit Oza, MD (Lon) FRCP FRCPC
role: PRINCIPAL_INVESTIGATOR
References:
citation: McMullen M, Karakasis K, Loembe B, Dean E, Parr G, Oza AM. DUETTE: a phase II randomized, multicenter 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 poly(ADP-ribose) polymerase (PARP) inhibitor maintenance treatment. Int J Gynecol Cancer. 2020 Nov;30(11):1824-1828. doi: 10.1136/ijgc-2020-001694. Epub 2020 Sep 2.