CTRI

Ovarian cancer (OC) poses a looming pandemic, with a projected 50 percent increase in incidence and mortality by 2040. In India, more than 30,000 women die per year, and the numbers are rapidly increasing. After breast and cervix, it is the commonest gynaecological cancer and the costliest to treat with 5-year survival rates approximating 30-40 percent. The combination of late diagnosis, advanced stages at presentation, and high recurrence rates, represent a clinical unmet need. During the past decade, targeted therapies like PARP inhibitors (PARPi) have revolutionized the treatment paradigm and survival in OC both in frontline and recurrent settings (Phase 3 RCTs including ARIEL, SOLO, ATHENA and real-world evidence). The maximum benefit is seen in platinum sensitive cases, especially in the 50 to 60 percent of epithelial OC that harbor specific genetic mutations, such as BRCA1, BRCA2 and Homologous Recombination Deficiency (HRD). Rucaparib, also known as Rubraca, developed by the Newcastle University UK team was one of the first PARPi to enter anticancer clinical trials. Currently its generic form, is widely prescribed in India and is also a candidate for development by the made in India PARPi program (CSIR-HCP 40). Although BRCA or HRD testing and the use of PARPi have become the standard-of-care in developed countries and are publicly funded, these advancements are scarcely accessible in lower-resource-settings. Developing innovative strategies for affordable alternatives to bridge this gap in health-inequality, is the need of the hour.

There are several challenges for accessing and prescribing targeted therapies including PARPi, in India and in other LMICs. The currently recommended daily scheduling which is based on maximal tolerated dosing (MTD) in western populations, are much higher than the biological optimal dosing, and is beyond the affordability thresholds for many women globally (70 percent of ovarian cancer burden). This creates health-inequality, limiting access to a potentially life-saving treatment. Furthermore, PARPi-related haematological toxicities, pose additional challenges especially, in women with lower body weight or pre-existing anaemia. Both physical and financial toxicity, often leads to treatment discontinuation and subtherapeutic dosing due to random empirical dose reduction strategies, which may adversely affect the progression-free survival (PFS), overall survival (OS) and Quality-of-life (QoL). Trials are being conducted to address the same.

A novel dose-reduction strategy has been initiated by the study team, based on sound preclinical data originating from Newcastle University in the UK and continuing through successive bilateral Indo-UK grants, such as the DST-UKIERI grant for IPIROC 01 pre-clinical study and CRUK-DBT India seed- corn funding for the IPIROC 02 exploratory cohort study, which used intermittent dosing of generic Rucaparib in recurrent treatment settings. Based on the promising pilot data on response-rates and duration of response, a larger randomized study is proposed, to establish a proof-of-concept in maintenance settings. The aim is to develop affordable effective policies and outcome measures for OC treatment, that is relevant to resource-adapted-settings and are based on scientific pre-clinical data (PK-PD-PG) driven personalized, optimal scheduling strategies. Developing cost-efficient novel trial designs will generate a template for future pragmatic studies in low resource settings and will support made-in-India or regional drug-development programmes.

Primary Objective: i. Proof of concept that Intermittent dosing of PARP-inhibitor-Rucaparib (IPIROC regimen) is an optimal and acceptable option for maintenance therapy in platinum-sensitive epithelial ovarian cancer with a favorable toxicity profile including financial toxicity and QoL.

Other objectives include: ii. Generating prospective data on PARPi use registry through a patient participatory model and study willingness-to-pay and financial toxicity of PARPi therapy iii. Implement pragmatic and cost-efficient approaches to trial design and conduct through novel strategies such as the R2CT strategy (Rationalizing and Reducing the Cost of Running Randomized Controlled Trials in resource restricted settings) and EASE model of implementation research, thereby leading to maximal inclusivity in recruitment and patient or provider advocacy iv. Translational outcome: Developing dose-reduction or toxicity reduction strategies customized to PK or PD or PG profile and functional HRD status.

Inclusion criteria: High grade serous ovarian or primary peritoneal or fallopian tube cancer (FIGO stage III or IV) with adequate performance status and organ function, who would be deemed suitable for prescription of maintenance PARPi in routine clinical practice (both frontline and recurrent settings) as a standard-of-care (SOC) i.e., i. HRD or BRCA positive for frontline maintenance after response to adjuvant platinum-based chemotherapy and ii. HRD or BRCA platinum-sensitive 1st relapse greater than 6 months after completion of last platinum-based chemotherapy and showing response (SD or PR or CR) to platinum rechallenge.

An umbrella master protocol is designed to study the toxicity and efficacy (non-confirmatory, non-inferiority) signal for the intervention (Intermittent PARPi Rucaparib regimen) as an acceptable maintenance therapy option in two different treatment settings (recurrent and frontline) in platinum sensitive BRCA or HRD positive high-grade serous OC, where the current SOC maintenance therapy is a daily PARPi regimen. It is a Pragmatic clinical trial using a patient participatory model that includes patients’ choice of inclusion in studies, ranging from Interventional (randomized controlled trial and non-randomized, single-arm intermittent dosing PARPi trial) and non-interventional (observational) study arms as contemporary controls (i.e., self-funded daily PARPi or non-PARPi maintenance strategies). A novel R2CT approach (Rationalizing and Reducing Cost of Running Randomized Controlled Trials in resource-adapted-settings) will be implemented to generate evidence in a pragmatic, academic setting and in a cost-efficient manner.

Setting 1: Recurrent setting: HRD or BRCA positive platinum-sensitive relapse, where maintenance PARPi is prescribed as SOC after response (CR or PR or SD) to platinum-based chemotherapy. Patient can choose to enroll between the trial options in this setting (Patient cards) which include one of the following:

· Phase 2 RCT with a 3:1 allocation ratio to Intermittent Rucaparib (Intervention) vs Daily Rucaparib (contemporary control). (Card A)

· Self-funded, physician or patient’s choice daily PARPi (any) observational cohort (Card C)

Setting 2: Frontline setting: PARPi maintenance therapy is considered as SOC for patients with HRD or BRCA positive, high-grade serous, ovarian or fallopian tube or primary peritoneal cancer, where response to platinum-based chemotherapy is obtained. Patient can choose to enroll amongst one of the trial options in this setting:

· Phase 2 RCT with randomized consent design with 3:1 allocation ratio, where patient can consent to receive either the intervention-intermittent Rucaparib (IPIROC regimen) or self-funded physician or patient’s choice of daily PARPi (control) as per original allocation, or can consent to choose the alternative arm. (Card A)

· Self-funded, physician or patient’s choice daily PARPi (any) observational cohort (Card C)

Patients not willing to participate in any of the above options will also have an opportunity to provide consent to the physicians or the hospital to provide data for the PARP registry (Card Z). All patients receiving PARPi from any of the above and in other settings (outside of this master protocol) will contribute to a PARPi registry generating contemporary and real-world data on PARPi use in ovarian cancer.

Primary outcome : 12 months PFS will be the primary efficacy endpoint in the recurrent setting and 12 or 24 months PFS for the frontline setting. Toxicity is a co-primary endpoint.

Secondary outcome includes 12 or 24-month QA-PFS, Time to symptoms or toxicity (TTST), QOL and MOST symptom trajectory, COST-PRO and cost-benefit analysis (CBA) for financial tolerability, patient satisfaction, fear of progression and translational endpoints. Exploratory endpoints include success of implementation and pragmatism for the R2CT strategy.

For the Recurrent setting, the Phase 2 RCT will include 200 patients. Using a 3:1 randomization between intermittent (intervention) and daily (control) arms and based on adaptation following interim analysis on toxicity, a minimum of 164 subjects (N=123 Intermittent arm and N=41 daily arm) are required as per power calculation. Additional numbers are added to account for approximately 20percent dropout rates.

For the Frontline setting, the Phase 2 RCT will include 150 patients (N=90 for the Intermittent arm, N=30 for the daily arm for 3:1 randomization and additional for approximately 20percent dropout rates.

The additional non-randomized observational arms (single arm intervention and contemporary controls) will continue to recruit patients throughout the duration of the study period and contribute to a registry data, both for the recurrent and frontline settings.

Multi-Centric in India spanning across all states and set-ups including rural and urban, government and private. International sites through IGCS, GCIG, APGOT networks.

Patients who satisfy the I E criteria and chose the RCT option for trial participation (Card A), will be randomized in 3:1 ratio to Intervention (Intermittent Rucaparib IPIROC regimen-600mg BD twice a week) vs Control (Daily PARPi regimen; Rucaparib 600 mg BD daily in recurrent setting and Physician’s choice daily PARPi regimen in the frontline setting). The randomization list will be generated in R (version 4.5.1) statistical software. Randomization stratification will be done for different sites, response to platinum (Complete or partial or stable disease), platinum free interval (PFI) and residual disease status at surgery in the frontline setting.

A patient will be discontinued from treatment if any of the following might occur:

i. Patient withdraws consent on their own request or on request of their legally authorized representative ii. Any (Serious) Adverse Event or other health phenomenon that would lead to a non- compromising safety risk for the patient according to the investigator iii. A concomitant illness or condition that might affect clinical assessments and might lead to trial discontinuation according to the investigators’ discretion iv. Patient is pregnant at any time within the trial duration.

Clinical assessments for haematology, biochemistry (liver and renal function tests) will be done along with collection of blood and tissue samples for bio-banking and translational research. Biochemical progression will be measured by CA-125 and radiological progression will be measured by appropriate imaging techniques like CT or PET CT scans as per GCIG RECIST criteria. Only the discovery of a new lesion will determine if a patient with a CR at study enrollment has progressed. Disease assessment will be done as a part of routine clinical assessments, or if there is a serious medical condition as determined by the investigator leading to discontinuation of medication. Patients should continue to receive either Intermittent or Daily PARPi and evaluation by RECIST according to the protocol schedule, if the radiologic assessment does not demonstrate progression. Patients may reduce the number of disease assessments after participating in the trial for at least 12 months. Prior to reducing frequency, investigators should speak with sponsor’s medical monitor.

Adverse events (AEs), hematological or serum chemistry, bodyweight, concurrent medications or procedures, ECOG, and study drug adjustments will be included in safety evaluations. AEs and SAEs will be monitored until they are resolved, stabilized, or no longer require follow-up.

A schematic diagram representing the patient flow to randomized and non-randomized study arms using a patient participatory model (PPM) is described. Study specific informed consent will be obtained; Schedule of assessments are described in the Table distributed over 24 months at predefined intervals, aligned with study objectives. A checklist for each study visits and study procedures or schedules are developed.

Screening Phase: Screening will occur within 28 days before the first Rucaparib dose, after informed consent. Key assessments include demographics, medical and family history, physical examination, ECOG status, labs (CBC, LFT, RFT, CA-125), ECG, and pregnancy test. Tumor imaging and tissue sample availability will be confirmed, and all relevant clinical data will be collected to determine eligibility.

Schedule-Based Monitoring: Before each Rucaparib dose, physical exams, ECOG status, vital signs, labs, AE or SAE monitoring, and drug accountability will be performed. Rucaparib is taken twice daily with water, with or without food, and adherence is documented in a dosing diary.

Translational Sample Collection: Blood samples for PARP analysis will be taken at pre-defined timepoints (pre-dose, 24h, 72h, 168h) for pharmacokinetic (PK) and Pharmacodynamic (PD) assays. FFPE tissue block will be collected for biobanking, HRD assays, immunohistochemistry, and other translational research analyses.

Tumor Scan: Imaging will be done during screening. Subsequent imaging will occur only upon biochemical progression, clinical signs or symptoms or as per physician’s discretion as a part of routine clinical pathways.

Clinical Laboratory Investigations: Routine labs (haematology, MCV, CA-125, renal & liver function) will be done locally through certified labs; specialized assays (BRCA or HRD) are performed by central laboratories (Detailed in a Pathology Charter or Lab Manual). All labs will be reviewed by investigators before treatment starts.

Vital Signs: Vital signs—blood pressure, pulse, and temperature—will be taken as per schedule. Abnormal readings may prompt further evaluation.

12-Lead Electrocardiograms: ECGs will be done at screening and end of treatment. These will be analyzed locally and used to assess cardiac safety.

Body Weight and Height: Height is measured once at screening; weight is monitored regularly as per institutional policy. These measurements aid safety monitoring.

Physical Examinations: Complete exams are conducted at screening, with focused assessments at later visits. All major body systems will be evaluated for safety.

ECOG Performance Status: ECOG is assessed at screening and treatment end by the same personnel, if possible (Appendix 1). Accurate scoring is essential, particularly for study eligibility

Safety Evaluations: Safety will be monitored continuously from consent through 28 days post-treatment. AEs will be graded using NCI CTCAE v5.0 (Appendix 6) and recorded in the eCRF (section 23, page 32). Laboratory and clinical assessments will help track toxicity and drug-related effects.

Adverse Event Assessment: All AEs, including physical, psychological, and lab abnormalities, will be assessed and documented from consent to 28 days after final dose. CTCAE v5.0 will be used for grading. Ongoing SAEs will be followed until stabilization or resolution.

Efficacy Evaluations: Efficacy will be measured using imaging, CA-125, and RECIST criteria. Timing and modality consistency is critical for objective assessments.

Tumor Assessments: Imaging is done at screening and every alternate cycle. Consistent imaging techniques are required for lesion tracking. Brain metastases, if present, will be assessed regularly.

Tumor Markers: CA-125 will be monitored at baseline, each treatment cycle start, and at the end of treatment. It serves as a biochemical marker of response.

End of Treatment Visit: After the last Rucaparib dose, assessments will include physical exam, ECOG status, CA-125, labs, AE review, and tumor scans if discontinuation was not due to radiologic progression. Drug accountability will also be completed.

End of Study Visit: This visit occurs 28 (±3) days after the last Rucaparib dose. It includes AE monitoring and tumor scans (if not completed earlier). Ongoing SAEs are followed until resolution

Adverse Event Management: AEs include physical, lab, or psychological symptoms occurring during the study. Not all AEs are drug-related; pre-existing condition fluctuations are excluded. CTCAE v5.0 grading is used for standardization. SAEs include death, life-threatening conditions, or hospitalization. Grade greater than or equal to 3 AEs per CTCAE are considered serious. Exceptions apply for planned admissions or social circumstances. AEs will be classified as related or unrelated to Rucaparib or other PARPi. Causality depends on timing, biological plausibility, and exclusion of other causes. Only related AEs are recorded in the study. TEAEs are those beginning after the first study dose and within 28 days of the last. Only TEAEs and TE-SAEs will be analyzed and reported in IPIROC. SUSARs are serious, unexpected adverse reactions linked to the study drug. These must be reported quickly, especially if fatal or life-threatening, within 7 days of awareness.

Recording of AEs: Only TEAEs will be documented in the REDCap eCRF under PI supervision. Entries will follow CTCAE v5.0, with detailed start or stop dates and symptom types. Lab-based and clinical AEs are included.

Recording of SAEs: All TE-SAEs graded greater than or equal to 3 must be recorded in REDCap with complete dates. Documentation will follow standard templates and reporting timelines.

Reporting of SAEs: SAEs must be reported immediately to the PI. A multidisciplinary team (MDT) will assess each SAE and determine relatedness and reporting obligations.

Reporting of SUSARs: The PI will review each SAE to determine if it is a SUSAR. Fatal or life-threatening SUSARs must be reported within 7 days of detection, with follow-up action documented.

Outcome of AEs: Each AE will be documented with its outcome: resolved, improved, ongoing, or death. Lost-to-follow-up and residual effects will also be noted.

Annual Safety Report: An annual safety summary will be compiled and submitted to authorities. This report will include cumulative AE or SAE data and safety signals, aligned with regulatory standards

The following tools will be used for assessing Health related Quality of Life (HR-QoL): EORTC QLQ-C30, OV28, EQ5D-5L. A minimalist approach will be conducted for the frequency of evaluation as detailed in Table 2 and will be supplemented with the GCIG-MOST symptom questionnaire evaluation at additional interim time points. In addition, patient satisfaction to treatment will be evaluated using LMSQ and fear of cancer recurrence will be evaluated using the FCRI-SF questionnaires.

A willingness-to-pay (WTP) questionnaire will be used to study the cost benefit analysis (CBA) of daily and intermittent regimens using a contingent valuation method (CVM) and later exploring other methodologies (Discrete choice experiment). FACIT-COST questionnaire will be used to assess financial toxicity to PARPi treatment for daily and intermittent regimens. Questionnaires will be administered at baseline and at 12-month time period since start of treatment. Additionally, cost-effectiveness analysis (CEA) will be carried out for the IPIROC regimen using Markov or Micro-simulation models. Cost-analysis will take health and personal health services perspective.

Apart from the interventional endpoints, the IPIROC 03 study will also be addressing observational endpoints which will be generated by Physician and Patient surveys and qualitative studies, PARP inhibitor registry, and a PARPi systematic review. Also, patients choosing for self-funded Daily PARPi or Physician’s choice of maintenance or No maintenance at the initial visit (during card selection) will be considered as an observational cohort and will be consented for providing clinical and QoL data, analyzed as an observational endpoint. TwiC and Registry based RCT models could be developed from these observational cohorts.

A novel KolGOTRG EASE model will be evaluated to study the key performance indicators (KPI) for the success of the R2CT approach and EASE of a pragmatic implementation using the KolGOTRG PRAGMATIC framework which conforms to PRECIS 2 tool. The Site Feasibility criteria and scoring matrix for equity, diversity and inclusion in recruitment is developed to maximize inclusion. A visual pie chart will continually assess recruitment challenges and develop patient or provider advocacy strategies including patient empathy approaches and continual assessments. Minimal datasets are used.

For the purpose of study, a number of biological samples will be collected and processed including peripheral blood mononuclear cells for PD, whole blood for genomic analyses, plasma for PK, circulating biomarkers and genotyping, as well as archived tumor tissue to determine HRD status and validation of functional HRD assay. All samples will be stored in a single centralized biobank with a biobank consent, to maintain the integrity of sample, for long term secure storage and future analysis and discovery of biomarkers. The objective of this research is to develop pilot data towards developing a PK or PD or PG and functional HRD status guided scheduling strategy for intermittent PARPi in the future, that can allow further dose de-escalation in selected patients. Samples will be collected at recurrence, wherever feasible to complement studies aiming to explore PARPi resistance with IPIROC regimen.

This is a phase 2 study intended for non-confirmatory, non-inferiority signal finding in efficacy and toxicity (including quality adjusted endpoints) for the IPIROC regimen and comparative analysis against other contemporary observational cohorts.

Setting 1: BRCA or HRD HGSC patients eligible for maintenance PARPi in platinum sensitive 1^st recurrence

The historical median is 16.6mths which approximates a 12month PFS of 57.5 to 60 percent in the control group (daily dosing group) [ARIEL 3 study]. Assuming an acceptable non-inferiority (NI) margin of 10percent, measured as the uncertainty in the 12-month PFS estimate in the control group, a sample size of 123 is required for the intermittent dosing (intervention) group, based on the upper 95percent CI. This margin is lower than the 25percent detriment in efficacy margin accepted by the patient group Sarbojaya during a PPI workshop conducted in India during 2021, as an acceptable trade-off for opting for a low dose regimen that holds promise of lower toxicity and better affordability. A 3:1 randomization allocation strategy to avoid selection bias in recruitment, will require 41 patients to receive daily PARPi (non- comparator control). The total sample size for the RCT platform (Card A) is therefore 164 and assuming a 20bpercent drop rate, 200 patients will be recruited. The additional contemporary control (observational) cohorts or platforms as per patient choice (Card B-study funded single arm intermittent regimen; Card C-self-funded daily SOC Physician’s choice PARPi regimen and Card D- self funded other non-PARPi maintenance or no maintenance regimens) will be recruited in parallel as a part of a PARPi registry and data from these observational cohorts will also be analyzed alongside the data obtained from the RCT. Stratification factors will include disease status after response to platinum (stable partial or complete response), platinum free interval (greater than 12 months), and the treating institution with the method of randomization being minimization.

The incidence of hematological Grade 3 toxicity is expected to be approximately 20-25 percent in the SOC group. The upper 95 percent CI for an 8percent reduction in Grade 3 toxicity will exclude 25 percent and a 7percent reduction will exclude a 20 percent Grade 3 rate based on a sample size of approximately 120 patients. The accrual period is expected to be 2 years with a further 1-year follow-up.

This pragmatic Phase 2 study will allow for revision of the primary objectives (if deemed necessary) through the deliberations of an independent data safety and monitoring committee (DSMC) which will periodically review the study. The recruitment process is expected to be completed within a two-year time period by enrolling approximately 7 or 8 patients per month for the treatment arm and 1 to 2 patients for the control arm. This approach aims to maintain a balanced and consistent patient distribution between the experimental and control groups throughout the study. For simplicity, we consider all the Center in the study to be equal performers, and there is no disparity among patient populations from one Center to another. For the non-comparison observational cohorts, no specific predefined sample size is calculated, and analysis will be performed on the total number of patients that are obtained until the targeted sample size for trial population is obtained.

In addition, a group sequential adaptive design approach will be tested in parallel, for periodic assessments of toxicity around the following accrual targets:

Setting 2. BRCA or HRD HGSC patients eligible for PARPi in frontline setting

A similar patient-participatory approach will be followed in the frontline setting too. The toxicity profile as well as 12 and 24 months PFS will be assessed. Patients may choose to receive the intermittent regimen either as a single arm study or through a randomized consent design process, where randomization (3:1) to either a study-funded intermittent regimen or a self-funded daily regimen (Physician’s choice) will be offered. Patients can then provide consent to remain on the allocated arm or change to a study arm of their choice. Stratification factors will include residual disease at surgery and response to platinum. Other contemporary controls include a self-funded daily regimen arm or a physician’s or patient’s choice other maintenance or no maintenance arm. After 12 months, patients will be assessed for their preference and options to either continue with the existing regimen for another 12 months or cross over to another regimen, but will require self-funding for all the options, if additional funding is not secured. Based on the initial assessment at 12 months, the study team will explore the possibility of whether the intermittent arm can be continued to be funded for additional 12 months or after the conclusion of the Phase 2 study, the same protocol can be extended to develop a phase 2 or 3 RCT in the frontline setting.

Considerations for Sample size estimation for the Phase 2 RCT in the frontline setting: This is a comparative randomized pragmatic phase 2 design to estimate the size of the Hazard ratio (HR) comparing intermittent Rucaparib to SOC. The ATHENA study reported a 2-year PFS rate for 2-year PFS for frontline Rucaparib maintenance of 56 percent translating to a median PFS rate of 28.7 months. A design allowing for a 10 percent non-inferiority margin (NI) at 24 months based on a 56 percent PFS rate translates to a hazard ratio (HR) of 1.34. Assuming a duration of accrual of 24 months with patients followed up for at least 36 months, a total sample size of 120 patients will be randomized using a 3:1 allocation with 90 patients enrolled in the experimental arm and 30 patients in the standard of care (SOC) arm. The expected number of progressions based on 90 and 30 patients by 24 months are 40 and 14 respectively. The sample sizes in the two groups together with a 90 percent confidence interval yield a confidence interval of [HR divided by 1.67 to HR multiplied by 1.67]. If the upper limit is less than 1.677, then we would conclude that the signal for intermittent Rucaparib compared to SOC to be non-inferior to SOC and worthy of further investigation in a larger study. This approach has been adapted from that used by Motzer et al. While it is recognized that this study is underpowered to detect such an effect, the size of the difference may still have sufficient clinical activity to warrant further investigation but a decision to investigate further would be based on additional information related to the observed HR, toxicity, QoL and other outcomes.

The co-primary endpoints will be analyzed as proportion of the incidence of Grade 3 hematological toxicity experience and the 12-month or 24-month PFS determined from the method of Kaplan-Meier. Proportions and their corresponding one-sided 95 percent CI will be provided in the intervention group. Estimates for contemporary control will provide guidance as to whether there is sufficient evidence for further investigation of this regimen. Consideration of benefit will also include compliance, financial burden relief, ease if follow-up etc. Exploratory analyses on the relationship between baseline variables and outcomes will be performed using t-test for continuous variables and chi-squared for categorical variables. Multivariate exploratory analyses will involve linear, logistic and proportional hazards regression methods for continuous, binary and time-to event outcomes. No adjustment is planned for multiple comparison and no formal missing data imputation is envisaged.

Regulatory and ethical considerations: The study will comply with the protocol, SOPs, and GCP. Amendments require prior approval from the sponsor or PI. Any serious protocol or regulatory non-compliance will lead to corrective action or site termination. Serious breaches affecting subject safety or scientific validity must be reported within 24 hours to the sponsor or PI.

Approval of regulatory authority: The sponsor will seek approvals from BIORRAP, CTRI, HMSC prior to study initiation. Each site must obtain local IEC clearance before being activated. International sites require country-specific approvals. Data will be handled in compliance with HIPAA and India’s IT Act 2008.

Institutional Review Board, Scientific Advisory Board and Independent Ethics Committee Approval: The protocol is first reviewed by the Scientific Advisory Committee, and upon their approval, submitted to the Sponsor’s IEC with all required documents. Patient recruitment begins only after IEC and regulatory approvals are obtained. The investigator must submit annual progress reports and report SAEs or SUSARs promptly to the IEC.

Patient and Public Involvement or Engagement: PPI activities has been conducted through conceptualization to development of the study and will be continued throughout the study duration and dissemination process.

General aspects: All study-related documentation will comply with ICH-GCP, the Declaration of Helsinki, and local regulations. The Informed Consent Form (ICF) must be approved by the IRB or IEC and meet regulatory standards. The investigator is responsible for obtaining legally valid informed consent after explaining the study.

Informed consent process: Potential participants will receive the approved ICF and relevant study information; the consent process facilitated by AV aids involves detailed discussion of the study, risks, and voluntary nature of participation in one of the study options as patient chosen cards. Signed consent will be documented, and stored. Re-consent is required following protocol or ICF amendments.

Patient confidentiality: Patients will be identified using unique codes to maintain confidentiality. A separate identity list will be maintained securely by the country PI. Anonymized data may be shared with collaborators, ethics boards, and for publication purposes.

Study monitoring: Pre-study visits by the sponsor or CRO will assess site readiness, except when waived. Regular monitoring visits will continue through study closure. These visits ensure compliance and data integrity.

Review of documents: CRFs and source documents will be reviewed periodically by monitors per ICH-GCP. Investigators must inform the sponsor of any regulatory conflicts before starting the study. All findings must be resolved by the investigator during the study.

Data Management Plan: Data will be collected using REDCap, a secure, HIPAA-compliant platform hosted at MD Anderson enabling secure data entry, audit trails, and controlled access. Patient identifiers will be retained securely, and data may be archived indefinitely for future IRB-approved research. KolGOTRG secure IT domains and SOPs will be followed and audited to ensure data security, data transfer, data protection and data back-up.

Study termination and site closure: Study termination may occur due to safety concerns, ethical reasons, or sponsor decision. All relevant data must be documented for analysis. Communication with regulatory authorities and ethics committees will be ensured throughout the termination process.

Study Protocol amendments: All protocol changes must be approved by the PI and team, with documentation submitted to the IRB or IEC. Amendments complying with ICH-GCP and approved will be implemented.

Retention of study documents: Sites must maintain essential study documents per ICH E6 (R2) and SOPs. Documents include protocol versions, ethics approvals, translated materials, CVs, and SAE records. Records will be archived securely for at least 15 years post-study.

Quality control or Quality assurance: The sponsor and PI will implement QA or QC measures using KolGOTRG SOPs. These ensure study conduct and data reporting align with regulatory requirements. Regular checks will support protocol compliance.

Regulation statement: The study will follow national laws and ICH-GCP guidelines. Ethics committee approvals will be secured before initiation. The study will adhere to all applicable regulatory standards.

Recruitment, consent: Patients will be provided with detailed trial information and must sign informed consent forms. For illiterate participants, an independent witness will verify consent. Consent must be documented before any study-specific procedures begin.

Screening log: Center must maintain a screening log detailing eligible and ineligible cases. Reasons for exclusion must be documented. Logs will be anonymized and shared with KolGOTRG annually and at study completion.

Subject identification: Each patient will receive a unique ID for tracking in CRFs. Investigators will retain identifiable information for up to 15 years. Confidentiality will be strictly maintained throughout.

Withdrawal of individual subjects: Participants may withdraw anytime without penalty. Investigators can also withdraw subjects for medical reasons. Reasons for withdrawal will be recorded.

Replacement of individual subjects after withdrawal: Withdrawn patients prior to treatment start will be replaced. Those who discontinue for non-study reasons will also be replaced to maintain sample size.

Compensation for injury: The study is covered by insurance to provide compensation for injuries during the trial. Coverage applies during the study and for four years after its conclusion. It complies with Indian legal standards.

Ancillary and Post Trial Care: ROCK coordinating center will liaise with respective sites to ensure follow up.

Central data Center: Data will be entered into eCRFs developed by KolGOTRG and maintained by site Data Managers. Sites may input data directly or submit paper forms. Data Center will oversee access control and quality.

Handling and storage of data and documents: Study Coordinators and the Data Center will manage protocol development, SAE documentation, data review, coordinate data analysis and publication. All clinical queries will be addressed by the coordinating team.

Site Monitoring: Site monitoring will follow ICH-GCP for low-risk studies. Monitoring will check compliance, consent, data accuracy, and AE reporting. A study-specific monitoring plan will guide activities.

Central monitoring: The Data Center will analyze collected data centrally to identify anomalies or protocol violations. Queries will be sent to the local investigators for clarification. Irregularities will be tracked and resolved.

Quality Assurance: The study may be audited to ensure compliance with GCP and regulations. Investigators must provide time and access for audits. Regulatory inspections may also occur during or after the trial.

Amendments: Substantial amendments affecting safety or scientific value must be notified to the IEC. Non-substantial amendments will be recorded but not submitted. All changes will be documented by the sponsor.

Annual progress report: Investigators will submit annual study updates to ICMR and local IECs. Reports will include subject enrollment, SAE data, and protocol amendments. Timely submission is essential.

Temporary halt and (prematurely) end of study report: The sponsor must notify IEC and regulatory authorities of study completion or temporary halt. If terminated early, the sponsor must report within 15 days. A final study report will be submitted within one year.

Trial Management Group and Trial Steering Committee: Details will be available in specific charters.

Results will be published following scientific norms and GCIG guidelines. Final publications will be coordinated by study coordinators and statisticians at KolGOTRG. Authorship will depend on recruitment contributions, with fixed and flexible slots defined. Approval is required from principal investigators, following data maturity rules. Information will be disseminated at scientific meetings, patient support groups, funders and media. The protocol will be published with open access and will be available in relevant websites upon publication.

Risk Assessment: Key risks include adverse drug reactions and non-compliance with medication schedules. These risks can affect patient safety and trial outcomes. Early identification is essential.

Risk Analysis: Each risk will be assessed based on likelihood and impact. Risks will be categorized from low to high. This helps prioritize mitigation efforts.

Risk Mitigation: ADRs will be managed through robust monitoring protocols. Non-compliance will be addressed by daily adherence reminders and site training. Effective communication with patients will support compliance.

Potential issues of concern: The interventional arm is treatment de-escalation, therefore likely to reduce toxicity, suffering and cost of treatment and no patient harm is anticipated. A wider circulation pf patient leaflet and study information for this publicly funded project will ensure that patient participation is entirely voluntary and accepting the risk for unknown efficacy signal associated with the new regimen. Patients also have the choice to choose the standard of care daily treatment, if they wished so as a part of the master protocol. We anticipate some degree of provider bias in not choosing to offer a dose de-escalation study to patients who can afford treatment or when competing interests exist favoring prescribing daily dosage of PARPi. There could be a remote possibility when the costly trial drug, provided free of cost is swapped by a cheaper daily generic PARPi,

A CAPA (corrective and preventive action) log will be generated for risks identified and will be periodically reviewed in the ROCK MDT and trial management board meetings. A pilot runner phase for the 1st patient from 1^st batch of recruiting sites (maximum 20 patients) will be conducted to ensure smooth site-specific operations and identify what works best or customized requirements for the site. The periodic evaluation of the recruitment wheel, RITE (Rapid Iterative Test and Evaluation) and the EASE matrix for implementation (early diagnosis and treatment of challenges) will address areas for provider and patient advocacy and action to improve rates or experience of recruitment and retention in the trial.

Investigational medical product(s): All forms of PARP inhibitor use in the trial is registered by the Drug Controller General of India (DCGI) including the generic forms of Rucaparib (BDParib) and Olaparib. The COI from the drug manufacturer (BRR Pharmaceuticals) has been obtained. All the study drug has been purchased upfront to ensure that there will be no interruption in the supply throughout the study duration for funding reasons. The study duration has been fixed to ensure trial drug batch and LOT numbers do not vary significantly and vendor management is defined. The trial drug bottle will have IPIROC study sticker or barcode so that it cannot be used or sold outside of trial purposes.

A data-safety monitoring board (DSMB) will be formed to assess the safety and efficacy of the interventions and monitor the overall conduct of the trial with a view to safeguard patient interests. The DSMB will review the report of SAEs and SUSARs and evaluate the number and ratio of patients developing Grade 3 toxicity at predefined intervals (statistical analysis plan).

1. Mathur R, Swaminathan S. National ethical guidelines for biomedical and health research involving human participants. Indian J Med Res. 2018;148(3):279-83.

2. Vergote I, Gonzalez-Martin A, Lorusso D, et al. Clinical research in ovarian cancer: consensus recommendations from the Gynecologic Cancer InterGroup. Lancet Oncol. 2022;23(8):e374-e384.

3. Chan AW, Boutron I, Hopewell S, et al. SPIRIT 2025 statement: updated guideline for protocols of randomised trials. Lancet. 2025;405(10491):e19-e27.

4. Cabasag CJ, Fagan PJ, Ferlay J, et al. Ovarian cancer today and tomorrow: a global assessment by world region and Human Development Index using GLOBOCAN 2020. Int J Cancer. 2022;151(9):1352-61.

5. Chaturvedi M, Krishnan S, Das P, et al. Descriptive epidemiology of ovarian cancers in India: a report from National Cancer Registry Programme. Indian J Gynecol Oncol. 2023;21(1):1-7.

6. Lheureux S, Gourley C, Vergote I, Oza AM. Epithelial ovarian cancer. Lancet. 2019;393(10177):1240-53.

7. Colombo N, Sessa C, du Bois A, et al. ESMO–ESGO consensus conference recommendations on ovarian cancer: pathology and molecular biology, early and advanced stages, borderline tumours and recurrent disease. Ann Oncol. 2019;30(5):672-705.

8. Ledermann J, Harter P, Gourley C, et al. Olaparib maintenance therapy in platinum-sensitive relapsed ovarian cancer. N Engl J Med. 2012;366(15):1382-92.

9. Swisher EM, Lin KK, Oza AM, et al. Rucaparib in relapsed, platinum-sensitive high-grade ovarian carcinoma (ARIEL2 Part 1): an international, multicentre, open-label, phase 2 trial. Lancet Oncol. 2017;18(1):75-87.

10. Coleman RL, Oza AM, Lorusso D, et al. Rucaparib maintenance treatment for recurrent ovarian carcinoma after response to platinum therapy (ARIEL3): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2017;390(10106):1949-61.

11. Moore K, Colombo N, Scambia G, et al. Maintenance olaparib in patients with newly diagnosed advanced ovarian cancer. N Engl J Med. 2018;379(26):2495-505.

12. Monk BJ, Parkinson C, Lim MC, et al. A randomized, phase III trial to evaluate rucaparib monotherapy as maintenance treatment in patients with newly diagnosed ovarian cancer (ATHENA-MONO/GOG-3020/ENGOT-ov45). J Clin Oncol. 2022;40(34):3952-64.

13. González-Martín A, Pothuri B, Vergote I, et al. Niraparib in patients with newly diagnosed advanced ovarian cancer. N Engl J Med. 2019;381(25):2391-402.

14. Shirley M. Rucaparib: a review in ovarian cancer. Target Oncol. 2019;14(2):237-46.

15. Curtin NJ. The development of rucaparib/Rubraca®: a story of the synergy between science and serendipity. Cancers (Basel). 2020;12(3):564.

16. Plummer R. Evolution of the development of PARP inhibitors. Cancer Treat Res. 2023;186:1-11.

17. Plummer R, Jones C, Middleton M, et al. Phase I study of the poly(ADP-ribose) polymerase inhibitor, AG014699, in combination with temozolomide in patients with advanced solid tumors. Clin Cancer Res. 2008;14(23):7917-23.

18. Reid F, Adams T, Adel RS, et al. The Every Woman Study™ low- and middle-income countries edition protocol: a multi-country observational study to assess opportunities and challenges to improving survival and quality of life for women with ovarian cancer. PLoS One. 2024;19(5):e0298154.

19. Murray J, Thomas H, Berry P, et al. Tumour cell retention of rucaparib, sustained PARP inhibition and efficacy of weekly as well as daily schedules. Br J Cancer. 2014;110(8):1977-84.

20. Smith HL, Willmore E, Mukhopadhyay A, et al. Differences in durability of PARP inhibition by clinically approved PARP inhibitors: implications for combinations and scheduling. Cancers (Basel). 2022;14(22):5559.

21. Mukhopadhyay A, Ghosh T, Bhattacharjee D, et al. Intermittent PARP inhibitor regimen in ovarian cancer (IPIROC): a proof-of-concept exploratory pragmatic study (IPIROC#02) using generic rucaparib with pharmacodynamic assessment. J Clin Oncol. 2025;43(16_suppl):e17597.

22. Simon GE, Shortreed SM, DeBar LL. Zelen design clinical trials: why, when, and how. Trials. 2021;22(1):398.

23. Motzer RJ, Hutson TE, Olsen MR, et al. Randomized phase II trial of sunitinib on an intermittent versus continuous dosing schedule as first-line therapy for advanced renal cell carcinoma. J Clin Oncol. 2012;30(12):1371-7.

24. Mukhopadhyay A, Ghosh T, Bhattacharjee D, et al. Intermittent PARP inhibitor regimen in ovarian cancer (IPIROC): origin and feasibility of implementing a proof-of-concept exploratory study. Int J Gynecol Cancer. 2023;30(Suppl 4):A197-8.

25. Abdul-Aziz S, Chakraborty D, Bhattacharya A, et al. Patient and public involvement in designing a willingness to pay survey for a PARP inhibitor de-escalation study IPIROC in ovarian cancer: a UK-India experience. Int J Gynecol Cancer. 2024;35(Suppl 8):A83-4.

26. Olsen JA, Smith RD. Theory versus practice: a review of ’willingness-to-pay’ in health and health care. Health Econ. 2001;10(1):39-52.

27. Adjei N, Sun C, Estrada G, et al. Assessing cancer-related financial toxicity and association with patient-reported outcomes among patients with recurrent ovarian cancer. Int J Gynecol Cancer. 2023;33(Suppl 3):A68-9.

28. Guy H, Walder L, Fisher M. Cost-effectiveness of niraparib versus routine surveillance, olaparib and rucaparib for the maintenance treatment of patients with ovarian cancer in the United States. Pharmacoeconomics. 2019;37(3):391-405.

29. Gonzalez R, Havrilesky LJ, Myers ER, et al. Cost-effectiveness analysis comparing "PARP inhibitors-for-all" to the biomarker-directed use of PARP inhibitor maintenance therapy for newly diagnosed advanced stage ovarian cancer. Gynecol Oncol. 2020;159(2):483-90.

30. Kumari S, Bhattacharjee D, Ghosh T, et al. Representing EDI in gynaecological oncology academic clinical trials in India: IPIROC trial framework. Int J Gynecol Cancer. 2024;35(Suppl 8):A304-5.

31. Sehouli J, Boer J, Brand AH, et al. How to optimize and evaluate diversity in gynecologic cancer clinical trials: statements from the GCIG Barcelona meeting. Int J Gynecol Cancer. 2024;34(11):1677-84.

32. Mukhopadhyay A, Elattar A, Cerbinskaite A, et al. Development of a functional assay for homologous recombination status in primary cultures of epithelial ovarian tumor and correlation with sensitivity to poly(ADP-ribose) polymerase inhibitors. Clin Cancer Res. 2010;16(8):2344-51.

33. Mukhopadhyay A, Plummer ER, Elattar A, et al. Clinicopathological features of homologous recombination-deficient epithelial ovarian cancers: sensitivity to PARP inhibitors, platinum, and survival. Cancer Res. 2012;72(22):5675-82.

Treatment with PARPi (daily or Intermittent schedule) starts at the 168-hour (7^th day) time point after blood has been collected for the final time point of the PD assay. Patient may also re consent for Card A (frontline). Patient surveys will be customized, adapted and added as platforms throughout the duration of the study to avoid duplication and synergize with parallel contemporary patient surveys in ovarian cancers

Procedures	Enrolment or Baseline Visit 1, Day 0 or -7 days	Visit 2 (3 sessions) 24 or 72 or 168 hour post single dose rucaparib	Visit 3 Month 1 ± 1 week	Visit 4 Month 3 ± 3 weeks	Visit 5 Month 6 ± 3 weeks	Visit 6 Month 9 ± 3 weeks	Visit 7 Month 12 ± 3 weeks	Visit 8 Month 15 ± 3 weeks	Visit 9 Month 18 ± 3 weeks	Visit 10 Month 21 ± 3 weeks	Final Visit Month 24 ± 3 weeks
Informed Consent	×
Demographics	×
Medical History	×	×		×	×		×		×	×	×
Family History	×
Physical Examination	×			×			×		×		×
ECOG status	×		×	×	×		×		×		×
Prior or concomitant Medication (if any)	×			×	×	×	×	×	×	×	×
CBC, LFT, RFT, CA-125	×		×	×	×	×	×	×	×	×	×
Blood or Tissue sample for biobanking	×	×
Adverse Events Evaluation *			×	×	×	×	×	×	×	×	×
EORTC QLQ-C30, OV-28, EQ-5D-5L	×				×		×				×
GCIG-MOST			×			×			×
WTP, CAM and Patient surveys		×					×
FACIT-COST		×					×
Empathy program		×
LMSQ					×		×
FCRI	×			×			×
Complete CRF	×			×	×	×	×	×	×	×	×
PARPi compliance			×	×	×	×	×	×	×	×	×
Routine follow up at physician discretion	×		×	×	×	×	×	×	×	×	×