Refining Adjuvant Treatment IN Endometrial Cancer Based On Molecular Features (RAINBO)

• ClinicalTrials.gov Identifier: NCT05255653
• Recruitment Status: Recruiting
• First Posted: February 24, 2022
• Last Update Posted: October 19, 2022
• Sponsor: Leiden University Medical Center
• Collaborators: Institute Gustave Roussy (sponsor p53abn-RED trial); Leiden University Medical center (sponsor MMRd-GREEN trial); University College London (sponsor NSMP-ORANGE trial); Canadian Clinical Trials Group (sponsor POLEmut-BLUE trial); Dutch Gynaecological Oncology Group; Comprehensive Cancer Centre The Netherlands; Cancer Research UK & UCL Cancer Trials Centre; Dutch Cancer Society; AstraZeneca
• Information provided by (Responsible Party): Carien Creutzberg, Leiden University Medical Center

Study Description

Brief Summary:

The RAINBO umbrella program consists of four clinical trials investigating new adjuvant therapies in endometrial cancer patients. Eligible patients will be assigned to one of the four RAINBO trials based on the molecular profile of their cancer:

• p53 abnormal endometrial cancer patients to the p53abn-RED trial
• mismatch repair deficient endometrial cancer patients to the MMRd-GREEN trial
• no specific molecular profile endometrial cancer patients to NSMP-ORANGE trial
• POLE mutant endometrial cancer patients to the POLEmut-BLUE trial

Condition or disease	Intervention/treatment	Phase
Endometrial Cancer	Drug: Olaparib; Radiation: Pelvic external beam radiotherapy; Drug: Chemotherapy; Drug: Durvalumab; Drug: Medroxyprogesterone Acetate; Drug: Megestrol Acetate; Other: Observation	Phase 2; Phase 3

Detailed Description:

The p53abn-RED trial is an international, multicenter, phase III randomised trial wherein adjuvant chemoradiation followed by olaparib for two years is compared to adjuvant chemoradiation.

The MMRd-GREEN trial is an international, multicenter, phase III randomised trial wherein adjuvant pelvic external beam radiotherapy combined with and followed by durvalumab for one year is compared to adjuvant pelvic external beam radiotherapy.

The NSMP-ORANGE trial is an international, multicenter, phase III randomised trial wherein adjuvant pelvic external beam radiotherapy followed by progestogens for two years is compared to adjuvant chemoradiation.

The POLEmut-BLUE trial is an international, multicenter, single arm, phase II trial wherein safety of de-escalation of adjuvant therapy is investigated: no adjuvant therapy for stage I-II disease and no adjuvant therapy or pelvic external beam radiotherapy only for stage III disease.

The overarching RAINBO research project will combine the data and tumor material of the four RAINBO clinical trials to perform translational research and compare molecular profile-based adjuvant therapy to standard adjuvant therapy in terms of effectiveness, toxicity, quality of life and cost utility.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 1611 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: Umbrella trial wherein eligible patients are assigned to one of four parallel running clinical trials. Three of four trials are randomised controlled trials and one is a single arm clinical trial.
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Refining Adjuvant Treatment IN Endometrial Cancer Based On Molecular Features: the p53abn-RED Trial, the MMRd-GREEN Trial, the NSMP-ORANGE Trial and the POLEmut-BLUE Trial
• Actual Study Start Date: November 11, 2021
• Estimated Primary Completion Date: January 1, 2030
• Estimated Study Completion Date: January 1, 2031

Arms and Interventions

Arm	Intervention/treatment
Experimental: p53abn-RED trial: experimental; Adjuvant chemoradiation followed by olaparib (lynparza), 300 mg twice daily, for two years	Drug: Olaparib; 300 mg twice daily for two years; Other Name: Lynparza; Radiation: Pelvic external beam radiotherapy; 45.0-48.6 Gy; 1.8-2.0 Gy per fraction, 5 fractions a week; Other Name: EBRT; Drug: Chemotherapy; Preferably concurrent and adjuvant according to the PORTEC-3 schedule: two cycles of intravenous cisplatin 50mg/m² in the first and fourth week of the pelvic external beam radiotherapy followed by four cycles of intravenous carboplatin AUC 5 and paclitaxel 175 mg/m² at 21-day intervals.; Other Names: Cisplatin; Carboplatin; Paclitaxel
Active Comparator: p53abn-RED trial: control; Adjuvant chemoradiation	Radiation: Pelvic external beam radiotherapy; 45.0-48.6 Gy; 1.8-2.0 Gy per fraction, 5 fractions a week; Other Name: EBRT; Drug: Chemotherapy; Preferably concurrent and adjuvant according to the PORTEC-3 schedule: two cycles of intravenous cisplatin 50mg/m² in the first and fourth week of the pelvic external beam radiotherapy followed by four cycles of intravenous carboplatin AUC 5 and paclitaxel 175 mg/m² at 21-day intervals.; Other Names: Cisplatin; Carboplatin; Paclitaxel
Experimental: MMRd-GREEN trial: experimental; Adjuvant pelvic external beam radiotherapy combined with and followed by durvalumab, 1500 mg intravenous once every 4 weeks for in total 1 year (13 cycles)	Radiation: Pelvic external beam radiotherapy; 45.0-48.6 Gy; 1.8-2.0 Gy per fraction, 5 fractions a week; Other Name: EBRT; Drug: Durvalumab; 1500 mg intravenous once every 4 weeks for in total 1 year (13 cycles) starting within the first week of radiotherapy,; Other Name: Imfinzi
Active Comparator: MMRd-GREEN trial: control; Adjuvant pelvic external beam radiotherapy	Radiation: Pelvic external beam radiotherapy; 45.0-48.6 Gy; 1.8-2.0 Gy per fraction, 5 fractions a week; Other Name: EBRT
Experimental: NSMP-ORANGE trial: experimental; Adjuvant pelvic external beam radiotherapy followed by oral progestagens (medroxyprogesterone acetate or megestrol acetate) for two years	Radiation: Pelvic external beam radiotherapy; 45.0-48.6 Gy; 1.8-2.0 Gy per fraction, 5 fractions a week; Other Name: EBRT; Drug: Medroxyprogesterone Acetate; Oral medroxyprogesterone acetate for two years; Other Name: Progestogen; Drug: Megestrol Acetate; Oral medroxyprogesterone acetate for two years; Other Name: Progestogen
Active Comparator: NSMP-ORANGE trial: control; Adjuvant chemoradiation	Radiation: Pelvic external beam radiotherapy; 45.0-48.6 Gy; 1.8-2.0 Gy per fraction, 5 fractions a week; Other Name: EBRT; Drug: Chemotherapy; Preferably concurrent and adjuvant according to the PORTEC-3 schedule: two cycles of intravenous cisplatin 50mg/m² in the first and fourth week of the pelvic external beam radiotherapy followed by four cycles of intravenous carboplatin AUC 5 and paclitaxel 175 mg/m² at 21-day intervals.; Other Names: Cisplatin; Carboplatin; Paclitaxel
Experimental: POLEmut-BLUE; no adjuvant therapy for stage I-II disease and no adjuvant therapy or pelvic external beam radiotherapy only for stage III disease	Radiation: Pelvic external beam radiotherapy; 45.0-48.6 Gy; 1.8-2.0 Gy per fraction, 5 fractions a week; Other Name: EBRT; Other: Observation; No adjuvant treatment; Other Names: Watchful waiting; No adjuvant treatment

Outcome Measures

Primary Outcome Measures :

1. p53abn-RED trial [ Time Frame: 3 years ]
   Recurrence-free survival
2. MMRd-GREEN trial [ Time Frame: 3 years ]
   Recurrence-free survival
3. NSMP-ORANGE trial [ Time Frame: 3 years ]
   Recurrence-free survival
4. POLEmut-BLUE trial [ Time Frame: 3 years ]
   Pelvic recurrence-free survival

Secondary Outcome Measures :

1. Recurrence-free survival [ Time Frame: 5 years ]
   All RAINBO trials
2. Pelvic recurrence-free survival [ Time Frame: 5 years ]
   All RAINBO trials
3. Vaginal recurrence-free survival [ Time Frame: 3 years, 5 years ]
   All RAINBO trials
4. Endometrial cancer-specific survival [ Time Frame: 3 years, 5 years ]
   All RAINBO trials
5. Overall survival [ Time Frame: 3 years, 5 years ]
   All RAINBO trials
6. Treatment-related toxicity - according to CTCAE v5.0 [ Time Frame: 3 years, 5 years ]
   All RAINBO trials
7. Health-related quality of life - Assessed using the EORTC QLQ-C30 questionnaire [ Time Frame: 3 years, 5 years ]
   All RAINBO trials
8. Health-related quality of life - Assessed using the EORTC QLQ-EN24 questionnaire [ Time Frame: 3 years, 5 years ]
   All RAINBO trials

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: Female sex
• Accepts Healthy Volunteers: No

Criteria

Participants of the four RAINBO trials should be eligible according to the inclusion and exclusion criteria of both the overarching RAINBO trials program and the clinical trial that they are assigned to based on the molecular profile.

Inclusion Criteria of the overarching RAINBO program:

• Histologically confirmed diagnosis of endometrial cancer (EC) of the following histotypes: endometrioid endometrial carcinoma, serous endometrial carcinoma, uterine clear cell carcinoma, dedifferentiated and undifferentiated endometrial carcinoma, uterine carcinosarcoma and mixed endometrial carcinomas of the aforementioned histotypes.
• Full molecular classification performed following the diagnostic algorithm described in WHO 2020 (5th Edition, IARC, Lyon, 2020)
• Hysterectomy and bilateral salpingo-oophorectomy with or without lymphadenectomy or sentinel node biopsy, without macroscopic residual disease after surgery
• No distant metastases as determined by pre-surgical or post-surgical imaging (CT scan of chest, abdomen and pelvis or whole-body PET-CT scan)
• WHO performance status 0, 1 or 2
• Expected start of adjuvant treatment (if applicable) within 10 weeks after surgery
• Patients must be accessible for treatment and follow-up
• Written informed consent for participation in one of the RAINBO trials, permission for the contribution of a tissue block for translation research and permission for the use and sharing of data for the overarching research project according to the local Ethics Committee requirements.

Exclusion Criteria overarching RAINBO program:

• History of another primary malignancy, except for non-melanoma skin cancer, in the past 5 years
• Prior pelvic radiation

The p53abn-RED trial

Inclusion criteria:

• p53 abnormal EC
• Histologically confirmed stage I (with invasion) II or III EC
• WHO Performance score 0-1
• Body weight > 30 kg

• Adequate systemic organ function:

  • Creatinine clearance (> 40 cc/min): Measured creatinine clearance (CL) >40 mL/min or Calculated creatinine CL>40 mL/min by the Cockcroft-Gault formula (Cockcroft and Gault 1976) or by 24-hour urine collection for determination of creatinine clearance.
  • Adequate bone marrow function : hemoglobin >9.0 g/dl, Absolute neutrophil count (ANC) ≥1.0 x 109/l, platelet count ≥75 x 109/l.
  • Adequate liver function: bilirubin ≤1.5 x institutional upper limit of normal (ULN). This will not apply to patients with confirmed Gilbert's syndrome (persistent or recurrent hyperbilirubinemia that is predominantly unconjugated in the absence of hemolysis or hepatic pathology), who will be allowed only in consultation with their physician, AND ALT (SGPT) and/or AST (SGOT) ≤2.5 x ULN

Exclusion criteria:

• Pathogenic POLE mutation(s)
• Mismatch repair deficiency
• Major surgical procedure (as defined by the investigator) within 28 days prior to the first dose of the IP
• History of allogenic organ transplantation
• Uncontrolled intercurrent illness, including but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, interstitial lung disease, serious chronic gastrointestinal conditions associated with diarrhea, or psychiatric illness/social situations that would limit compliance with study requirement, substantially increase risk of incurring AEs or compromise the ability of the patient to give written informed consent
• Any previous treatment with a PARP inhibitor, including olaparib
• History of active primary immunodeficiency
• History or evidence of hemorrhagic disorders within 6 months prior to randomization
• Patients with myelodysplastic syndrome/acute myeloid leukemia history or with features suggestive of MDS/AML
• Previous allogenic bone marrow transplant or double umbilical cord blood transplantation (dUCBT)
• Active infection, including: tuberculosis (clinical evaluation that includes clinical history, physical examination and radiographic findings, and TB testing in line with local practice), hepatitis B (known positive HBV surface antigen (HBsAg) result), hepatitis C, or human immuno-deficiency virus (positive HIV 1/2 antibodies). Patients with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody [anti-HBc] and absence of HBsAg) are eligible. Patients positive for hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA.
• Concomitant use of known strong CYP3A inhibitors (eg. itraconazole, telithromycin, clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, indinavir, saquinavir, nelfinavir, boceprevir, telaprevir) or moderate CYP3A inhibitors (eg. ciprofloxacin, erythromycin, diltiazem, fluconazole, verapamil). The required washout period prior to starting olaparib is 2 weeks.
• Concomitant use of known strong (eg. phenobarbital, enzalutamide, phenytoin, rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and St John's Wort) or moderate CYP3A inducers (eg. bosentan, efavirenz, modafinil). The required washout period prior to starting olaparib is 5 weeks for enzalutamide or phenobarbital and 3 weeks for other agents.
• Patients unable to swallow orally administered medication and patients with gastrointestinal disorders likely to interfere with absorption of the study medication.
• Medical or psychological condition which in the opinion of the investigator would not permit the patient to complete the study or sign meaningful informed consent.

The MMRd-GREEN trial

Inclusion criteria:

• Mismatch repair deficient EC
• Histologically confirmed Stage III EC or stage II EC with substantial lympovascular space invasion (LVSI)
• WHO Performance score 0-1
• Body weight > 30 kg

• Adequate systemic organ function:

  • Creatinine clearance (> 40 cc/min): Measured creatinine clearance (CL) >40 mL/min or Calculated creatinine CL>40 mL/min by the Cockcroft-Gault formula (Cockcroft and Gault 1976) or by 24-hour urine collection for determination of creatinine clearance.
  • Adequate bone marrow function : hemoglobin >9.0 g/dl, Absolute neutrophil count (ANC) ≥1.0 x 109/l, platelet count ≥75 x 109/l.
  • Adequate liver function: bilirubin ≤1.5 x institutional upper limit of normal (ULN). <<This will not apply to patients with confirmed Gilbert's syndrome (persistent or recurrent hyperbilirubinemia that is predominantly unconjugated in the absence of hemolysis or hepatic pathology), who will be allowed only in consultation with their physician.>> AND ALT (SGPT) and/or AST (SGOT) ≤2.5 x ULN

Exclusion criteria:

• Pathogenic POLE mutation(s)
• Major surgical procedure (as defined by the Investigator) within 28 days prior to the first dose of investigational medicinal product (IMP)
• History of allogenic organ transplantation
• Uncontrolled intercurrent illness, including but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, interstitial lung disease, serious chronic gastrointestinal conditions associated with diarrhea, or psychiatric illness/social situations that would limit compliance with study requirement, substantially increase risk of incurring AEs or compromise the ability of the patient to give written informed consent.
• Any previous treatment with a PD(L)1 inhibitor, including durvalumab.
• Receipt of live attenuated vaccine within 30 days prior to the first dose of durvalumab. Note: Patients, if enrolled, should not receive live vaccine whilst receiving IP and up to 30 days after the last dose of IMP.

• Current or prior use of immunosuppressive medication within 14 days before the first dose of durvalumab with the exceptions of:

  • Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra articular injection).
  • Systemic corticosteroids at physiologic doses not to exceed <<10 mg/day>> of prednisone or its equivalent.
  • Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication).
• History of active primary immunodeficiency

• Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease [e.g., colitis or Crohn's disease], diverticulitis [with the exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome. The following are exceptions to this criterion:

  • Patients with vitiligo or alopecia
  • Patients with hypothyroidism (e.g., following Hashimoto syndrome)stable on hormone replacement
  • Any chronic skin condition that does not require systemic therapy
  • Patients without active disease in the last 5 years may be included but only after consultation with the study physician.
• Active infection including tuberculosis (clinical evaluation that includes clinical history, physical examination and radiographic findings, and TB testing in line with local practice), hepatitis B (known positive HBV surface antigen (HBsAg) result), hepatitis C, or human immuno-deficiency virus (positive HIV 1/2 antibodies). Patients with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody [anti-HBc] and absence of HBsAg) are eligible. Patients positive for hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA.
• Medical or psychological condition which in the opinion of the investigator would not permit the patient to complete the study or sign meaningful informed consent.

The NSMP-ORANGE trial

Inclusion criteria:

• NSMP EC
• Histologically confirmed stage II EC with substantial LVSI or stage III EC
• ER positive EC
• WHO performance status 0-1

Exclusion criteria:

• Pathogenic POLE mutation(s)
• Mismatch repair deficiency
• p53 abnormality

The POLEmut-BLUE trial

Inclusion criteria:

• Pathogenic POLE mutation(s)
• Histologically confirmed stage I-III EC
• Patient consent must be appropriately obtained in accordance with applicable local and regulatory requirements. Each patient must sign a consent form prior to enrollment in the trial to document their willingness to participate. A similar process must be followed for sites outside of Canada as per their respective cooperative group's procedures.
• Patients must be accessible for treatment and follow up. Patients enrolled on this trial must be treated and followed at the participating centre. Investigators must assure themselves the patients enrolled on this trial will be available for complete documentation of the treatment, adverse events, and follow-up
• Patients must agree to return to their primary care facility for any adverse events which may occur through the course of the trial.

Exclusion criteria:

- Inability to be registered on study within 10 weeks of hysterectomy procedure

Contacts and Locations

Contacts

Contact: Carien L Creutzberg, MD PhD; +31 71 52 65539; c.l.creutzberg@lumc.nl

Contact: Nanda Horeweg, MD PhD; +31 71 52 65539; n.horeweg@lumc.nl

Locations

Canada

The POLEmut-BLUE trial: Princess Margaret Cancer Centre, University of Toronto; Not yet recruiting

Toronto, Canada

Contact: Kathy Han, MD PhD Kathy.Han@rmp.uhn.ca

The POLEmut-BLUE trial: University of British Columbia; Recruiting

Vancouver, Canada

Contact: Jessica N McAlpine, MD PhD Jessica.Mcalpine@vch.ca

France

The p53abn-RED trial: Institute Gustave Roussy; Not yet recruiting

Villejuif, France

Contact: Alexandra Leary, MD PhD alexandra.LEARY@gustaveroussy.fr

Netherlands

The MMRd-GREEN trial: Leiden University Medical Center; Recruiting

Leiden, Netherlands, 2333ZA

Contact: Judith R Kroep, MD PhD +31 71 526 5095 j.r.kroep@lumc.nl

Contact: Merve Kaya, MD +31 71 529 9661 m.kaya@lumc.nl

United Kingdom

The NSMP-ORANGE trial: Barts Health NHS Trust; Not yet recruiting

London, United Kingdom

Contact: Melanie E Powell, MD PhD melanie.powell10@nhs.net

The NSMP-ORANGE trial: Manchester Academic Health Science Centre, St Mary's Hospita; Not yet recruiting

Manchester, United Kingdom

Contact: Emma J Crosbie, MD PhD Emma.Crosbie@manchester.ac.uk

Sponsors and Collaborators

Leiden University Medical Center

Institute Gustave Roussy (sponsor p53abn-RED trial)

Leiden University Medical center (sponsor MMRd-GREEN trial)

University College London (sponsor NSMP-ORANGE trial)

Canadian Clinical Trials Group (sponsor POLEmut-BLUE trial)

Dutch Gynaecological Oncology Group

Comprehensive Cancer Centre The Netherlands

Cancer Research UK & UCL Cancer Trials Centre

Dutch Cancer Society

AstraZeneca

Investigators

• Principal Investigator: Alexandra Leary, Md PhD; Institute Gustave Roussy, Villejuif, France (p53abn-RED trial)
• Principal Investigator: Judith R Kroep, MD PhD; Leiden University Medical Center, Leiden, The Netherlands (MMRd-GREEN trial)
• Principal Investigator: Melanie E Powell, Md PhD; Barts Health NHS Trust, London, United Kingdom (NSMP-ORANGE trial)
• Principal Investigator: Emma J Crosbie, Md PhD; St Mary's Hospital, Manchester, United Kingdom (NSMP-ORANGE trial)
• Principal Investigator: Kathy Han, Md PhD; Princess Margaret Cancer Centre, University of Toronto, Toronto, Canada (POLEmut-BLUE trial)
• Principal Investigator: Jessica N McAlpine, Md PhD; University of British Columbia,Vancouver, Canada (POLEmut-BLUE trial)

More Information

Publications:

IMPLEMENTATION OF COLLABORATIVE TRANSLATIONAL RESEARCH (TRANSPORTEC) FINDINGS IN AN INTERNATIONAL ENDOMETRIAL CANCER CLINICAL TRIALS PROGRAM (RAINBO). T Bosse, M Powell, E Crosbie, A Leary, J Kroep, K Han, J Mcalpine, N Horeweg, S De Boer, M De Bruyn, R Nout, V Smit, HW Nijman, N Singh, H Mackay, R Edmondson, L Mileshkin, D Church, H Kitchener, CL Creutzberg. Int J Gynecol Cancer 2021;31(Suppl 3):A1-A395. DOI: 10.1136/ijgc-2021-ESGO.171

• Responsible Party: Carien Creutzberg, prof, Leiden University Medical Center
• ClinicalTrials.gov Identifier: NCT05255653
• Other Study ID Numbers: RAINBO; ENGOT-en14-1,2,3,4 ( Other Identifier: ENGOT )
• First Posted: February 24, 2022
• Last Update Posted: October 19, 2022
• Last Verified: October 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: Following the planned translational work in the RAINBO programme and publications, the translational research (TR) committee will open up the sample collection to external researchers. Access will be granted following completion of a research proposal form and approval by the TR committee chaired by Dr. Tjalling Bosse. All external researchers will be expected to demonstrate funding for their project and ethics approval. Data will be made available as required through data sharing agreements. The following will be reviewed when considering applications for data sharing and sample access: data and sample use is in-keeping with patient consent, the proposed project has scientific value, with defined objectives and study plan, trial data are appropriate for the intended purpose, acknowledgement of the RAINBO Programme in all publications that arise from the data sharing, compliance with legal and regulatory requirements as applicable and patient confidentiality maintained at all times.
• Supporting Materials: Study Protocol
• Time Frame: The study protocols of the four trials will be made made available on the trial's websites by the time the trials open
• Access Criteria: Public

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Carien Creutzberg, Leiden University Medical Center:

Endometrial Cancer; Molecular risk factors; Olaparib; Durvalumab; Progestagens; Chemoradiation; Radiotherapy; Observation; p53; MMRd; NSMP; POLE

Additional relevant MeSH terms:

Endometrial Neoplasms; Uterine Neoplasms; Genital Neoplasms, Female; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Uterine Diseases; Cisplatin; Carboplatin; Durvalumab; Olaparib; Medroxyprogesterone Acetate; Megestrol; Megestrol Acetate; Medroxyprogesterone; Progestins; Antineoplastic Agents; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents, Immunological; Poly(ADP-ribose) Polymerase Inhibitors; Enzyme Inhibitors; Contraceptives, Oral, Hormonal; Contraceptives, Oral; Contraceptive Agents, Female; Contraceptive Agents; Reproductive Control Agents; Physiological Effects of Drugs; Contraceptive Agents, Hormonal; Contraceptives, Oral, Synthetic; Contraceptive Agents, Male