Delayed Initiation of Olaparib Maintenance Therapy in Platinum Sensitive Recurrent Ovarian Cancer

• ClinicalTrials.gov Identifier: NCT04377087
• Recruitment Status: Recruiting
• First Posted: May 6, 2020
• Last Update Posted: August 7, 2020
• Sponsor: Sarah E Taylor
• Collaborator: American Society of Clinical Oncology
• Information provided by (Responsible Party): Sarah E Taylor, University of Pittsburgh

Study Description

Brief Summary:

The purpose of this study is to test if delaying the start of the olaparib until there is a rise in a tumor marker called CA-125 will result in a longer time until the next or different treatment for the patient's cancer. The study will also evaluate how delaying the start of maintenance therapy will affect symptoms; physical functioning; quality of life; and impact on finances.

Condition or disease	Intervention/treatment	Phase
Ovarian Cancer	Drug: Olaparib	Phase 2

Detailed Description:

This is a Phase II trial will investigate if waiting until the time of chemical recurrence, denoted by rising CA125, to start a PARP inhibitor will lead to an improved time to next therapy with improved quality of life and at a lower financial toxicity.

PARP-I have shown efficacy as both monotherapy and as maintenance therapy. This trial will explore whether patients with recurrent ovarian cancer could derive the same efficacy benefit from a delayed start of a PARP-I compared to immediate maintenance therapy. Delayed start would have the benefit of sparing the physical, psychological, and financial toxicity associated with prolonged treatment. This approach would be particularly relevant in a population of platinum-sensitive patients who can have prolonged treatment-free intervals.

With widespread use of PARP-I, regardless of timing, understanding, and overcoming PARP-I resistance is becoming a major clinical need.

Enrollment will start within 8 weeks of completion of platinum-based treatment. Monitored with CA 125 levels every 28 days. Olaparib will be started when CA 125 rises by two-fold of their nadir value. Olaparib will be dosed at 300 mg orally twice a day, 28 days of treatment will be a cycle. Follow-up will consist of CA125 drawn every 28 days and CT scans obtained at doubling of CA- 125 and then every 12 weeks* to assess for recurrence or progression. Clinician- and patient-reported adverse events recorded every 28 days. Cancer-related worry and distress assessed every 28 days. Measures of quality of life and physical function, and financial toxicity assessed every 12 weeks.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 75 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase IIA Trial of Delayed Initiation of Olaparib Maintenance Therapy in Platinum Sensitive Recurrent Ovarian Cancer
• Actual Study Start Date: June 29, 2020
• Estimated Primary Completion Date: October 2023
• Estimated Study Completion Date: May 2024

Arms and Interventions

Arm	Intervention/treatment
Experimental: Olaparib; Olaparib dosed at 300mg orally twice daily, started when CA125 rises by two-fold of nadir value.	Drug: Olaparib; Olaparib is a potent oral poly (ADP-ribose) polymerase (PARP) inhibitor that induces synthetic lethality in BRCA1/2 deficient tumor cells through the formation of double-stranded DNA breaks which cannot be accurately repaired, which leads to disruption of cellular homeostasis and cell death.; Other Name: Lynparza™

Outcome Measures

Primary Outcome Measures :

1. Time to Next Therapy [ Time Frame: Up to 42 months ]
   The time to next therapy from completion of platinum-based therapy for treatment of recurrence until initiation of post-olaparib treatment.

Secondary Outcome Measures :

1. Progression-free Survival (PFS) [ Time Frame: Up to 42 months ]
   Progression-free survival (PFS) defined as time from enrollment until detected recurrence or progression of disease, via Response Evaluation Criteria in Solid Tumors , or death from any cause.. Per RECIST 1.1, Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progression).
2. Overall Survival (OS) [ Time Frame: Up to 42 months ]
   Overall survival as defined as the time from enrollment to death from any cause.
3. Adverse Events Possibly, Probably or Definitely Related to Treatment [ Time Frame: Up to 30 days after discontinuation of treatment (for individual patient) ]
   The rate of Serious Adverse Events per Common Terminology Criteria for Adverse Events (CTCAE) v5.0 that are possibly, probably or definitely related to study treatment.
4. Overall Response Rate (ORR) [ Time Frame: Up to 42 months ]
   The proportion of patients with a best overall response of Complete Response (CR) or Partial Response (PR), per Response Evaluation Criteria in Solid Tumors (RECIST v1.1). Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.
5. The Functional Assessment of Cancer Therapy + Ovarian-specific scale (FACT-O) [ Time Frame: Up to 42 months ]
   Health-related quality of life measured via The Functional Assessment of Cancer Therapy + Ovarian-specific scale (FACT-O). The FACT-O includes a list of statements that [other] people with ovarian cancer have said are important. The patient is asked to circle or mark one number per line to indicate their response as it applies to the prior 7 days. The scoring ranges from 0 (Not at all) to 4 (very much).
6. PROMIS Physical Function-20a [ Time Frame: Up to 42 months ]
   Physical function assessed through the PROMIS Physical Function-20a assesses self-reported performance of physical activities. The PROMIS includes a list of statements related to physical performance, with scores of 0 (Always) to 5 (Rarely).
7. Assessment of Survivor Concerns (ASC) Worry Subscale and Impact of Event Scale (IES-R) [ Time Frame: Up to 42 months ]
   The Assessment of Survivor Concerns (ASC) Worry Subscale and Impact of Event Scale (IES-R) will be used to measure worry and distress. The assessment includes a list of statements related to worry and stress experience during the patients prior, with responses ranging from 0 (Not at all) to 4 (Extremely). This assessment includes three subscales, the Intrusion subscale, the Avoidance subscale and the Hyperarousal subscale, which are each related to specific questions.
8. Modified Collection of Indirect and Non-medical Direct Costs (COIN) [ Time Frame: Up to 42 months ]
   Financial toxicity measured through (a) monetary measure using the Modified Collection of Indirect and Non-medical Direct Costs (COIN), (b) objective measure of financial burden assessed using Barrera et al's Economic Hardship questionnaire, and (c) subjective measure of financial distress will be gauged using the Comprehensive Score for Financial Toxicity (COST Measure).

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: Female
• Gender Based Eligibility: Yes
• Gender Eligibility Description: Gynecological cancers
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Patient has platinum-sensitive, recurrent ovarian, fallopian-tube or peritoneal cancer. Platinum sensitivity is defined as complete clinical remission after frontline chemotherapy lasting greater than 6 months
• Patient has completed at least 2 courses of platinum-based chemotherapy with a PR or CR as defined by the Response Evaluation Criteria in Solid Tumors (RECIST) v1.139 or a CA-125 response, according to Gynecological Cancer InterGroup (GCIG) criteria40
• BRCA testing required (results not needed for registration)
• ECOG performance status score of 0, 1, or 2 (See Appendix A)
• Life expectancy greater than 6 months
• Normal organ and marrow function as defined: Absolute neutrophil count (ANC) ≥ 1.5 x 109/L; Platelets ≥ 100 x 109/L; Hemoglobin (Hgb) ≥ 8 g/dL (blood transfusions to reach this amount are allowed); Serum creatinine ≤ 1.5 mg/dL; Total serum bilirubin ≤ 1.5 x ULN; AST and ALT ≤ 2.5 x ULN
• Able to take oral medication
• Not pregnant and not breastfeeding
• Able to understand and willingness to sign a written informed consent document
• Patients must be enrolled within 8 weeks of completing last cycle of chemotherapy

Exclusion Criteria:

• Patient has had a prior invasive malignancy diagnosed within the last five years (except [1] non-melanoma skin cancer or [2] prior in situ carcinoma of the cervix or breast [3] has been without evidence of invasive disease for greater than 3 years)
• Patients receiving any other investigational agents
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to olaparib
• Uncontrolled intercurrent illness that could affect their participation in the study including, but not limited to, ongoing or active infection; symptomatic congestive heart failure; unstable angina pectoris; cardiac arrhythmia; known inadequately controlled hypertension; significant pulmonary disease including dyspnea at rest, patients requiring supplemental oxygen, or poor pulmonary reserve; or psychiatric illness/social situations that would limit compliance with study requirements
• Impairment of gastrointestinal function or disease that may significantly alter the absorption of olaparib
• Patients who have received prior treatment with a PARP inhibitor
• History of noncompliance to medical regimens

Contacts and Locations

Contacts

Contact: Brenda L Steele, BSN; 412-641-3418; steebx@UPMC.EDU

Contact: Donna Haney; 412-389-5208; haneydl@upmc.edu

Locations

United States, Pennsylvania

Magee Women's Hospital of UPMC; Recruiting

Pittsburgh, Pennsylvania, United States, 15213

Contact: Aja Yacobucci, RN 412-641-6372 gasparovica@upmc.edu

Contact: Emily Staniszewski, RN 412-641-3578 staniszewskie@upmc.edu

Principal Investigator: Sarah Taylor, MD

Sponsors and Collaborators

Sarah E Taylor

American Society of Clinical Oncology

Investigators

• Principal Investigator: Sarah Taylor, MD; University of Pittsburgh

More Information

• Responsible Party: Sarah E Taylor, Assistant Professor of Medicine, University of Pittsburgh
• ClinicalTrials.gov Identifier: NCT04377087
• Other Study ID Numbers: HCC 19-164
• First Posted: May 6, 2020
• Last Update Posted: August 7, 2020
• Last Verified: August 2020

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: Yes

Keywords provided by Sarah E Taylor, University of Pittsburgh:

PARP-I; BRCA mutation; Epithelial ovarian cancer (EOC); Olaparib; platinum sensitive; recurrent ovarian carcinoma; Poly ADP-Ribose Polymerase (PARP) inhibitor.

Additional relevant MeSH terms:

Ovarian Neoplasms; Carcinoma, Ovarian Epithelial; Endocrine Gland Neoplasms; Neoplasms by Site; Neoplasms; Ovarian Diseases; Genital Neoplasms, Female; Urogenital Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Olaparib; Hypersensitivity; Adnexal Diseases; Endocrine System Diseases; Gonadal Disorders; Carcinoma; Immune System Diseases; Poly(ADP-ribose) Polymerase Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents