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WoO: Window of Opportunity Trial of Olaparib and Durvalumab in Histologically Proven EOC (WoO)

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ClinicalTrials.gov Identifier: NCT04644289
Recruitment Status : Not yet recruiting
First Posted : November 25, 2020
Last Update Posted : November 25, 2020
Sponsor:
Information provided by (Responsible Party):
AGO Research GmbH

Brief Summary:
This is a multi-center, prospective, open-label, phase II trial. Patients with suspected advanced ovarian cancer planned to undergo diagnostic laparoscopy for histologic confirmation and evaluation of disease spread will be registered into the trial after providing a 1st written informed consent.

Condition or disease Intervention/treatment Phase
Epithelial Ovarian Cancer Drug: olaparib Drug: durvalumab Phase 2

Detailed Description:

In total, 60 patients are planned to be enrolled in 2 consecutive cohorts (30 patients per cohort) into the trial.

After histologic confirmation of high-grade epithelial non-mucinous, non-clear cell ovarian cancer, patients will be treated in two consecutive cohorts (A, B) of 30 patients each, with

A) olaparib alone or B) olaparib in combination with durvalumab

Treatment allocation will take place in two consecutive cohorts rather than by randomization. This will allow to evaluate the safety and feasibility in a stepwise approach. A trial steering committee (TSC) meeting will take place between the cohorts to review safety and feasibility prior to starting the second cohort. The safety follow-up of the first cohort will take 90 days as of the first dose of therapy.

The window-of-opportunity treatment phase will be followed by primary debulking surgery and standard of care platinum based first-line chemotherapy at the discretion of the investigator.

After completion of first-line chemotherapy patients who have not progressed during first-line chemotherapy will be offered maintenance treatment with olaparib for 24 months (or according to label).

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 60 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Intervention Model Description: Patients will be treated in two consecutive cohorts (A, B) of 30 patients each, with A) olaparib alone or B) olaparib in combination with durvalumab. Treatment allocation will take please in two consecutive cohorts rather than by randomization. This will allow to evaluate the safety and feasibility in a step-wise approach. A trial steering committee (TSC) meeting will take place between the cohorts to review safety and feasibility prior to starting the second cohort. The safety follow-up of the first cohort will take 90 days as of the first dose of therapy.
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Window-of-opportunity Proof-of-concept, Non-randomized, Open-label Phase II Trial of Olaparib Given Alone (Cohort A) or in Combination With Durvalumab (Cohort B) Prior to Primary Debulking Surgery in Histologically Proven High-grade Epithelial Ovarian Cancer (EOC)
Estimated Study Start Date : July 2021
Estimated Primary Completion Date : April 2026
Estimated Study Completion Date : November 2027


Arm Intervention/treatment
cohort A - olaparib monotherapy
Olaparib tablets 2 × 300 mg per day for 3 weeks prior to surgery until one day prior to surgery or withdrawal of informed consent and as maintenance for 24 months after completion of primary therapy (chemotherapy).
Drug: olaparib
Olaparib tablets are administrated orally 300 mg twice daily.
Other Name: Lynparza

cohort B - olaparib + durvalumab combination
Olaparib tablets 2 × 300mg per day for 4 weeks plus durvalumab 1500mg iv as a single dose prior to surgery (corresponding to 1 single cycle).
Drug: olaparib
Olaparib tablets are administrated orally 300 mg twice daily.
Other Name: Lynparza

Drug: durvalumab
Durvalumab is administered 1500mg iv as a single dose prior to surgery (corresponding to 1 single cycle) .
Other Name: Imfinzi




Primary Outcome Measures :
  1. Feasibility of the WoO procedure for olaparib alone (cohort a) & olaparib in combination with durvalumab (cohort b) [ Time Frame: Between registration into the trial until 60 days after surgery or 60 days after the originally planned surgery date in case of switch of therapeutic strategy. ]

    Defined as the successful completion of the WoO therapy:

    • Relative dose intensity (RDI) of ≥80%
    • No treatment-related surgical delays
    • Adherence to therapeutic strategy
    • Lack of clinical progression prior to primary debulking surgery
    • No treatment-related toxicities of any grade that in the judgment of the investigator or surgeon significantly interfered with the subject's optimal perioperative management


Secondary Outcome Measures :
  1. Safety of the WoO procedure [ Time Frame: Between registration into the trial until 60 days after surgery or 60 days after the originally planned surgery date in case of switch of therapeutic strategy. ]
    Evaluated by the proportion of patients who experience any adverse event (CTCAE v5.0), of a grade ≥3.

  2. Proportion of circulating tumor DNA (ctDNA) Mutation positive patients [ Time Frame: At baseline ]
    Proportion of ctDNA mutation positive patients at baseline above a predefined a cut-off (copies/ml).

  3. CDR21 [ Time Frame: At day 21 ]
    Circulating DNA ratio at day 21 (CDR21) defined as the ratio of mutation abundance at day 21 relative to baseline of the mutant ctDNA allele with the highest abundance (mutant copies/ml) at baseline.


Other Outcome Measures:
  1. Progression free survival (PFS) [ Time Frame: From registration until progression or death or date of LPLV whichever occurs first. Depending on the time point of inclusion into the trial the expected maximum follow-up time for an individual patient might range between 2.5 and 4,6 years. ]
    Defined as the time from registration into the trial (PIC2) until progression defined as progressive disease according to RECIST or Gynecological Cancer Intergroup (GCIG) criteria or death without progression or clinical deterioration of performance status with associated signs of disease (e.g. bowel obstruction and non-measurable disease).



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

WoO pre-treatment (screening phase):

  1. Patients with presumed and previously untreated advanced stage ovarian cancer planned to undergo laparoscopy for histologic diagnosis and treatment planning
  2. Patients willing and able to comply with the study protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up
  3. Patients able and willing to provide a fresh frozen biopsy from laparoscopy as well as primary debulking for translational endpoints as well as serial liquid biopsies
  4. Patients able and willing to provide formaldehyde-fixed paraffin embedded (FFPE) tissue samples from laparoscopy and primary debulking surgery
  5. Patients aged ≥18 years
  6. Patients must be capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol
  7. Provision of signed and dated, written ICF for the mandatory biomarker and genetic re-search as well as the clinical/therapeutic part of the study prior to any mandatory study specific procedures, sampling, and analyses
  8. Eastern cooperative oncology group (ECOG) performance status 0-1 (see Appendix 1)
  9. Patients must have a life expectancy ≥16 weeks
  10. Ability to take oral medication
  11. Postmenopausal or evidence of non-childbearing status for women of childbearing potential (WOCBP): negative urine or serum pregnancy test within 28 days of study treatment and confirmed prior to treatment on day 1.

    Postmenopausal is defined as:

    • Amenorrheic for 1 year or more following cessation of exogenous hormonal treatments
    • Luteinizing hormone (LH) and Follicle stimulating hormone (FSH) levels in the post menopausal range for women under 50
    • radiation-induced oophorectomy with last menses >1 year ago
    • chemotherapy-induced menopause with >1 year interval since last menses
    • surgical sterilisation (bilateral oophorectomy or hysterectomy)
  12. Women of childbearing potential (WOCBP) and their partners, who are sexually active, must agree to the use of 2 highly effective forms of contraception in combination. This should be started from the signing of the informed consent and continue throughout the period of taking study treatment and for at least 90 days after last dose of study drug(s), or they must totally/truly abstain from any form of sexual intercourse.

    WoO treatment phase:

  13. Confirmed advanced (FIGO IIB/III/IV) high-grade, non-mucinous, non-clear cell epithelial ovarian, fallopian tube or primary peritoneal cancer or known (BReast CAncer) BRCA mutation and any histologic type
  14. Planned primary debulking surgery after confirmation of diagnosis and disease evaluation during laparoscopy
  15. Body weight >30kg
  16. Patients must have normal organ and bone marrow function measured within 28 days prior to administration of study treatment as defined below:

    • Haemoglobin ≥10.0 g/dL with no blood transfusion in the past 28 days
    • Absolute neutrophil count (ANC) ≥1.5×10^9/L
    • Platelet count ≥100×10^9/L
    • Total bilirubin ≤1.5 × institutional upper limit of normal (ULN)
    • Aspartate aminotransferase (AST), serum glutamic oxaloacetic transaminase (SGOT) / alanine aminotransferase (ALT), serum glutamic pyruvate transaminase (SGPT) ≤2.5 × institutional upper limit of normal unless liver metastases are present in which case they must be ≤5×ULN. (cave: patients with intrahepatic metastases affecting liver function test might not be candidates for primary debulking surgery)
    • Patients must have creatinine clearance estimated of ≥51 mL/min using the Cockcroft-Gault equation or based on a 24 hour urine test:

Estimated creatinine clearance=((140-age [years])*weight (kg))/(serum creatinine (mg/dL)*72)(* 0,85)

Exclusion Criteria:

Medical conditions:

  1. Disease requiring urgent surgical intervention
  2. Evidence of significant uncontrolled concomitant disease that could affect compliance with the study protocol
  3. Significant uncontrolled symptom burden (e.g. but not necessarily limited to large volume ascites, shortness of breath on exertion, pain requiring opioid medication, signs of (sub)ileus
  4. Uncontrolled intercurrent illness, including but not limited to, ongoing or active infection, symptomatic congestive heart failure, recent (within 3 months) myocardial infarction, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, interstitial lung disease, uncontrolled major seizure disorder, unstable spinal cord compression, superior vena cava syndrome, 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.
  5. Other malignancy unless curatively treated with no evidence of disease for ≥5 years except: adequately treated non-melanoma skin cancer, curatively treated in situ cancer of the cervix, ductal carcinoma in situ (DCIS), Stage 1, grade 1 endometrial carcinoma. Patients with a history of localized triple negative breast cancer may be eligible, provided they completed their adjuvant chemotherapy more than three years prior to registration, and that the patient remains free of recurrent or metastatic disease (optional criteria that is dependent on the patient population under investigation).
  6. Resting electrocardiography (ECG) indicating uncontrolled, potentially reversible cardiac conditions, as judged by the investigator (eg., unstable ischemia, uncontrolled symptomatic arrhythmia, conges-tive heart failure, QTcF prolongation >500 ms, electrolyte disturbances, etc.), or patients with congenital long QT syndrome.
  7. Any unresolved toxicity NCI CTCAE Grade ≥2 from previous anticancer therapy with the exception of alopecia, vitiligo, and the laboratory values defined in the inclusion criteria

    a. Patients with irreversible toxicity not reasonably expected to be exacerbated by treatment with olaparib, durvalumab or the combination may be included only after consultation with the study physician

  8. Patients with myelodysplastic syndrome/acute myeloid leukemia or with features suggestive of myelodysplastic syndrome/acute myeloid leukemia (MDS/AML).
  9. Brain metastases or spinal cord compression. Patients with suspected brain metastases at screening should have an MRI (preferred) or CT each preferably with IV contrast of the brain prior to study entry
  10. Patients with symptomatic uncontrolled brain metastases. A scan to confirm the absence of brain metastases is not required. The patient can receive a stable dose of corticosteroids before and during the study as long as these were started at least 4 weeks prior to treatment. Patients with spinal cord compression unless considered to have received definitive treatment for this and evidence of clinically stable disease for 28 days.
  11. Evidence of central nervous system (CNS) or leptomeningeal metastases.
  12. Patients considered a poor medical risk due to a serious, uncontrolled medical disorder, non-malignant systemic disease or active, uncontrolled infection. Examples include, but are not limited to, uncontrolled ventricular arrhythmia, recent (within 3 months) myocardial infarction, uncontrolled major seizure disorder, unstable spinal cord compression, superior vena cava syndrome, extensive interstitial bilateral lung disease on High Resolution Computed tomography (HRCT) scan or any psychiatric disorder that prohibits obtaining informed consent.
  13. Patients unable to swallow orally administered medication and patients with gastrointestinal disorders or any status that might interfere with resorption of the respective study drugs, e.g. parenteral nutrition, short bowel syndrome likely to interfere with absorption of the study medication.
  14. Immunocompromised patients, e.g., patients who are known to be serologically positive for human immunodeficiency virus (HIV).
  15. History of active primary immunodeficiency
  16. 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 or hepatitis C.

    1. Active HBV is defined by a known positive HBsAg result. Patients with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody and absence of HBsAg) are eligible.
    2. Patients positive for HCV antibody are eligible only if polymerase chain reaction is negative for HCV RNA
  17. ECOG performance status (PS) ≥2 or general condition that might interfere with the compliance with the study protocol
  18. Known allergy or hypersensitivity to any of the study drugs or any of the study drug excipients.

    Prior / concomitant therapy:

  19. Prior antineoplastic therapy for ovarian, fallopian tube or primary peritoneal cancer
  20. Patients receiving any systemic chemotherapy or radiotherapy (except for palliative reasons) within 3 weeks prior to study treatment
  21. Any concurrent chemotherapy, investigational product (IP), biologic, or hormonal therapy for cancer treatment. Concurrent use of hormonal therapy for non-cancer-related conditions (e.g., hormone replacement therapy) is acceptable
  22. Patients planned for neoadjuvant chemotherapy or deemed unresectable at laparoscopy
  23. Concomitant use of known strong cytochrome P450 3A (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.
  24. 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
  25. Major surgery within 2 weeks of starting study treatment and patients must have recovered from any effects of any major surgery
  26. History of allogenic organ transplantation
  27. Previous allogenic bone marrow transplant or double umbilical cord blood transplantation (dUCBT).
  28. Patients with a known hypersensitivity to olaparib or any of the excipients of the product.
  29. Prior treatment with olaparib or any other poly [ADP-ribose] polymerase (PARP) inhibitor
  30. Whole blood transfusions in the last 120 days prior to entry to the study (packed red blood cells and platelet transfusions are acceptable, for timing refer to inclusion criteria no. 16)

    Other exclusions:

  31. Breast feeding women
  32. Involvement in the planning and/or conduct of the study
  33. Participation in another interventional clinical study with an investigational product during the last with the last 3 months.
  34. Concurrent enrolment in another clinical study, unless it is an observational (non-interventional) clinical study or during the follow-up period of an interventional study.
  35. Previous enrolment in the present study.
  36. Judgement by the investigator that the patient is unsuitable to participate in the study and the patient is unlikely to comply with study procedures, restrictions and requirements.

    Additional durvalumab specific exclusion criteria for cohort B:

  37. Receipt of the last dose of anticancer therapy (chemotherapy, immunotherapy, endocrine therapy, targeted therapy, biologic therapy, tumor embolization, monoclonal antibodies) ≤28 days prior to the first dose of study drug. If sufficient wash-out time has not occurred due to the schedule or pharmacokinetic (PK) properties of an agent, a longer wash-out period will be required, as agreed by AstraZeneca/MedImmune and the investigator.
  38. Any unresolved toxicity NCI CTCAE Grade ≥2 from previous anticancer therapy with the exception of alopecia, vitiligo, and the laboratory values defined in the inclusion criteria

    1. Patients with Grade ≥2 neuropathy will be evaluated on a case-by-case basis after consultation with the study physician.
    2. Patients with irreversible toxicity not reasonably expected to be exacerbated by treatment with durvalumab may be included only after consultation with the study physician.
  39. Any concurrent chemotherapy, IP, biologic, or hormonal therapy for cancer treatment. Concurrent use of hormonal therapy for non-cancer-related conditions (e.g., hormone replacement therapy) is acceptable.
  40. Major surgical procedure (as defined by the Investigator) within 28 days prior to the first dose of IP. Note: local surgery of isolated lesions for palliative intent is acceptable.
  41. History of allogenic organ transplantation.
  42. 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 [granulomatosis with polyangiitis, graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc]). The following are exceptions to this criterion:

    1. Patients with vitiligo or alopecia
    2. Patients with hypothyroidism (e.g., following hashimoto syndrome) stable on hormone replacement
    3. Any chronic skin condition that does not require systemic therapy
    4. Patients without active disease in the last 5 years may be included but only after consultation with the study physician
    5. Patients with celiac disease controlled by diet alone
  43. 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 (Adverse Events) AEs or compromise the ability of the patient to give written informed consent.
  44. 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
  45. History of leptomeningeal carcinomatosis
  46. Brain metastases or spinal cord compression. Patients with suspected brain metastases at screening should have an MRI (preferred) or CT each preferably with IV contrast of the brain prior to study entry.
  47. Mean QT interval corrected for heart rate using Fridericia's formula (QTcF) ≥470 ms calculated from 3 ECGs (within 15 minutes at 5 minutes apart)
  48. Active infection including tuberculosis (clinical evaluation that includes clinical history, physical examination and radiographic findings, and tuberculosis testing in line with local practice), hepatitis B (known positive hepatitis B virus (HBV) surface antigen (HBsAg) result), hepatitis C. Patients with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody [anti-hepatitis-B-core (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.
  49. Current or prior use of immunosuppressive medication within 14 days before the first dose of durvalumab. The following are exceptions to this criterion:

    1. Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra articular injection)
    2. Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or its equivalent
    3. Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication)
  50. Receipt of live attenuated vaccine within 30 days prior to the first dose of IP. Note: patients, if enrolled, should not receive live vaccine whilst receiving IP and up to 30 days after the last dose of IP.
  51. Patients who are pregnant or breastfeeding or patients of reproductive potential who are not willing to employ effective birth control from screening to 90 days after the last dose of durvalumab monotherapy.
  52. Prior randomisation or treatment in a previous durvalumab clinical study regardless of treatment arm assignment or other immunotherapies
  53. Patients who have received prior anti-programmed cell death-protein 1(PD-1), anti PD-L1 or anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4):

    1. Must not have experienced a toxicity that led to permanent discontinuation of prior immunotherapy.
    2. All AEs while receiving prior immunotherapy must have completely resolved or resolved to baseline prior to screening for this study.
    3. Must not have experienced a ≥Grade 3 immune related AE or an immune related neurologic or ocular AE of any grade while receiving prior immunotherapy. Note: Patients with endocrine AE of ≤Grade 2 are permitted to enroll if they are stably maintained on appropriate replacement therapy and are asymptomatic.
    4. Must not have required the use of additional immunosuppression other than corticosteroids for the management of an AE, not have experienced recurrence of an AE if rechallenged, and not currently require maintenance doses of >10 mg prednisone or equivalent per day.
  54. Patients planned for neoadjuvant chemotherapy (e.g. but not exclusively due to extend of disease spread or poor general condition etc.).
  55. (sub)ileus or signs of malignant bowel obstruction.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04644289


Contacts
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Contact: Friederike Kipkeew +49 201 959812-14 fkipkeew@ago-ovar.de

Sponsors and Collaborators
AGO Research GmbH
Investigators
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Principal Investigator: Frederik Marmé, MD Universitätsklinikum Mannheim, Frauenklinik
Additional Information:
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Responsible Party: AGO Research GmbH
ClinicalTrials.gov Identifier: NCT04644289    
Other Study ID Numbers: AGO-OVAR 27
2020-005101-12 ( EudraCT Number )
First Posted: November 25, 2020    Key Record Dates
Last Update Posted: November 25, 2020
Last Verified: November 2020

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by AGO Research GmbH:
Epithelial Ovarian Cancer
Olaparib
Durvalumab
Additional relevant MeSH terms:
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Ovarian Neoplasms
Carcinoma, Ovarian Epithelial
Endocrine Gland Neoplasms
Neoplasms by Site
Neoplasms
Ovarian Diseases
Adnexal Diseases
Genital Neoplasms, Female
Urogenital Neoplasms
Endocrine System Diseases
Gonadal Disorders
Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Durvalumab
Olaparib
Antineoplastic Agents, Immunological
Antineoplastic Agents
Poly(ADP-ribose) Polymerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action