Evaluation of Olaparib, Durvalumab, and UV1 as Maintenance Therapy in BRCA Wild-Type Recurrent Ovarian Cancer: A Randomized Clinical Trial
- Trial ID
- 2024-516327-14-00
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this randomized clinical trial is to compare the preliminary **efficacy** of maintenance treatment with **olaparib** (arm A) to that of olaparib plus **durvalumab** and **UV1** (arm C) in patients with recurrent **ovarian cancer** who are BRCA wild-type. This comparison is clinically relevant as it aims to determine the potential benefits of combining these agents in enhancing treatment outcomes for this patient population.
Secondary objectives include:
- Comparing the preliminary efficacy of maintenance treatment with olaparib plus durvalumab (arm B) to that of olaparib plus durvalumab and UV1 (arm C).
- Comparing the preliminary efficacy of maintenance treatment with olaparib to that of olaparib plus durvalumab and UV1 according to stratification factors.
- Evaluating Patient Reported Outcomes (PROs) in treatment arms.
- Comparing the preliminary efficacy of maintenance treatment according to **PD-L1** status.
- Evaluating safety in treatment arms.
- Describing genetic, molecular, and immunological mechanisms in blood and tumor of maintenance treatment.
- Exploring the efficacy of maintenance treatment in the molecular subgroups based on homologous recombination deficiency (HRD) status.
Participants
The clinical trial focuses on evaluating the efficacy of maintenance treatment in patients with **ovarian cancer**. The study population comprises exclusively female participants, as male subjects are not included. The age range of participants is categorized under codes 3 and 4, indicating that the study involves adult women. Participants are required to have a good general health status, as evidenced by an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1, and must have a life expectancy of at least 16 weeks. The trial does not provide specific information on the total number of participants, as this data was not disclosed by the sponsor. Selection criteria include the ability to swallow oral medications and post-menopausal status or evidence of non-childbearing potential. Participants must have completed at least two lines of chemotherapy and should not have progressed on the latest platinum-containing chemotherapy. The trial population is selected based on these criteria, ensuring that participants have a histologically confirmed diagnosis of epithelial ovarian, fallopian tube, or primary peritoneal cancer, excluding certain histologies. The study involves a vulnerable population, as indicated by the trial data.
Plans and Procedures
The clinical trial is designed to evaluate the efficacy of **olaparib**, **durvalumab**, and UV1 as maintenance therapy in patients with recurrent ovarian cancer. This is a randomized, double-blind, controlled trial, conducted in a Phase II setting. The trial aims to compare the progression-free survival (PFS) between different treatment arms, specifically arm A (olaparib alone) and arm C (olaparib combined with durvalumab and UV1). The study is expected to run from December 2021 to December 2029, with participant involvement lasting up to 36 months, depending on the treatment arm.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as age, performance status, and organ function. Following successful screening, participants will be randomized into one of the treatment arms. Regular follow-up visits will be scheduled to monitor treatment response, safety, and any adverse events. These visits will include assessments such as imaging studies, laboratory tests, and physical examinations. The end-of-study visit will occur after the completion of the treatment period or upon early termination.
Early termination from the study may occur if a participant experiences unacceptable toxicity, disease progression, or withdraws consent. Additionally, participants who do not comply with the study protocol or who are deemed by the investigator to be at risk may also be withdrawn. The trial will also explore secondary endpoints, including overall survival, time to subsequent therapies, and safety analysis, to provide a comprehensive evaluation of the treatment's impact on ovarian cancer.
Treatment
The clinical trial involves several experimental medications, each with specific administration protocols. **Leukine**, containing the active substance **sargramostim**, is provided as a **powder for solution for injection**. It is administered via **intradermal use** with a maximum daily dose of 75 µg, and the treatment period extends up to 20 days. The formulation is not pediatric, and the product is manufactured by Vestre Viken Health Trust.
**IMFINZI**, with the active substance **durvalumab**, is available as a **50 mg/mL concentrate for solution for infusion**. This medication is administered **intravenously** with a maximum daily dose of 1500 mg and a total dose limit of 36000 mg over a treatment period of 24 weeks. The product is developed by AstraZeneca AB and is not intended for pediatric use.
**Lynparza** is available in two formulations: **100 mg** and **150 mg film-coated tablets**, both containing the active substance **olaparib**. These tablets are administered **orally** with a maximum daily dose of 600 mg and a total dose limit of 657000 mg over a 36-week treatment period. The 100 mg tablets have a yellow film coat due to the absence of iron oxide, while the 150 mg tablets are identical to the investigational medicinal product (IMP) except for commercial debossing. Both formulations are produced by AstraZeneca AB and are not pediatric formulations.
**UV1** is a **powder for solution for injection** containing the active substances **alrefimotide, riletamotide, and tapderimotide**. It is administered via **intradermal use** with a maximum daily dose of 300 µg and a total dose limit of 300 µg over a 20-day treatment period. The product is developed by Ultimovacs ASA and is not intended for pediatric use.
Throughout the trial, participant compliance with dosing schedules is monitored to ensure adherence to the treatment protocols. No non-experimental treatments, such as standard-of-care therapy, placebo, or comparator treatments, are specified in the trial data provided.
Efficacy
The efficacy of the clinical trial will be assessed using several primary and secondary endpoints. The primary endpoint is **Progression-Free Survival (PFS)**, comparing arm A to arm C. Secondary endpoints include PFS for arm B versus arm C, overall survival (OS), time to first subsequent therapy (TFST), subsequent progression (PFS2), time to second subsequent therapy (TSST), objective response rate (ORR), and disease control rate (DCR). Additionally, patient-reported outcomes (PROs) and safety analysis will be evaluated. Exploratory endpoints will focus on the evaluation of changes in genetic, molecular, and immunological markers of response and/or resistance over time, as well as the correlation between these changes and efficacy in defined subgroups.
The efficacy parameters will be measured and collected at various timepoints throughout the trial. The assessments will be conducted using validated scales and laboratory tests, with some evaluations performed by a blinded independent central review (BICR) to ensure objectivity. The trial is designed to provide a comprehensive analysis of the efficacy of the treatments being investigated, with a focus on both clinical outcomes and patient-reported experiences.
Inclusion and Exclusion Criteria
Inclusion Criteria
- 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. The consent must be signed before the time of inclusion.
- Histologically diagnosed with epithelial ovarian, fallopian tube or primary peritoneal cancer, excluding mucinous or low-grade serous histology.
- Radiological or histological confirmation of relapse disease ≥ 6 months after penultimate chemotherapy.
- Patients who are non-gBRCAmut or tBRCAwt.
- Have completed at least two lines, but no more than 3 lines, of chemotherapy, which means that patients at first or second relapse with treatment free interval of more than 6 months on penultimate chemotherapy are eligible. See Figure 3. a. Patients must have completed at least 4 cycles of the latest platinum-containing chemotherapy.
- Be either: a. PARPi naive. b. Earlier treated with PARPi and not progressed during 6 months of PARPi therapy.
- Must not, in the opinion of the investigator, have progressed on, or after, latest platinumcontaining chemotherapy. This means that patients with CR, PR, SD or no evidence of disease are eligible. It should be documented on the post-treatment scan following completion of the last chemotherapy course.
- Patient consents to HRD test (Acceptable HRD tests: Myriad myChoice® CDx, Leuven HRD test, NOGGO GISv1, and TSO 500 HRD).
- Must be randomized in the study within 10 weeks of completion of the final dose of platinum-containing chemotherapy.
- Age ≥18 years.
- Body weight > 30 kg.
- Eastern Cooperative Oncology Group (ECOG) performance status 0-1 (Appendix 3).
- Must have a life expectancy ≥ 16 weeks.
- 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 (6,2 mmol/L) with no blood transfusion in the past 28 days. - Absolute neutrophil count (ANC) ≥ 1.5 x 109/L. ENGOT-OV56/NSGO-CTU-DOVACC EudraCT: 2020-004738-39 Version 4.0, 07.06.2024 Page 30 of 196 - Platelet count ≥ 100 x 109/L. - Total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN). - Aspartate aminotransferase (AST) (Serum Glutamic Oxaloacetic Transaminase (SGOT)) / Alanine aminotransferase (ALT) (Serum Glutamic Pyruvate Transaminase (SGPT)) ≤ 2.5 x institutional ULN unless liver metastases are present in which case, they must be ≤ 5x ULN. - Must have creatinine clearance estimated of ≥ 51 mL/min using the Cockcroft-Gault equation or based on a urine test: o Estimated creatinine clearance = [[140 – age(yr)] x weight(kg)] / [72 x serum Cr (mg/dL)] (multiply by 0.85 for women).
- Ability to swallow oral medications (tablets) without chewing, breaking, crushing, opening, or otherwise altering the product formulation.
- Post-menopausal or evidence of non-childbearing status for women of childbearing potential: negative urine or serum pregnancy test within 28 days of study treatment and confirmed prior to treatment on day 1. Post-menopausal is defined as: - Amenorrhoeic for 1 year or more following cessation of exogenous hormonal treatments. - Luteinizing hormone (LH) and Follicle stimulating hormone (FSH) levels in the postmenopausal 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).
Exclusion Criteria
- Previous use of immune checkpoint inhibitors. a. In case the patient has participated in an immune checkpoint inhibitor blinded study, the patient may be enrolled without unblinding.
- 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.
- Resting ECG indicating uncontrolled, potentially reversible cardiac conditions, as judged by the investigator (e.g., unstable ischemia, uncontrolled symptomatic arrhythmia, congestive heart failure, QTcF prolongation ≥ 470 ms, electrolyte disturbances, etc.), or patients with congenital long QT syndrome.
- Patients with myelodysplastic syndrome/acute myeloid leukemia or with features suggestive of MDS/AML.
- 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 if 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.
- 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.
- Concomitant treatment with bevacizumab within the last 3 weeks.
- Concomitant therapy with any other anticancer therapy or chronic use of systemic corticosteroids of more than 10mg prednisolone daily.
- Concomitant use of known strong CYP3A inhibitors (e.g., itraconazole, telithromycin, clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, indinavir, saquinavir, nelfinavir, boceprevir, telaprevir) or moderate CYP3A inhibitors (e.g., ciprofloxacin, erythromycin, diltiazem, fluconazole, verapamil). The required washout period prior to starting study treatment is 2 weeks.
- Concomitant use of known strong CYP3A inducers (e.g., phenobarbital, enzalutamide, phenytoin, rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and St John’s Wort) or moderate CYP3A inducers (e.g., bosentan, efavirenz, modafinil). The required washout period prior to starting study treatment is 5 weeks for enzalutamide or phenobarbital and 3 weeks for other agents.
- Previous allogeneic bone marrow transplant or double umbilical cord blood transplantation.
- Major surgery or significant traumatic injury within 28 days of randomization.
- Immunocompromised patients, e.g., patients who are known to be serologically positive for human immunodeficiency virus (HIV), patients with active hepatitis B (defined as having a positive hepatitis B surface antigen [HBsAg] test at screening) or hepatitis C. Patients with past hepatitis B virus (HBV) infection or resolved HBV infection (defined as having a negative HBsAg test and a positive antibody to hepatitis B core antigen [anti- HBc] antibody test) are eligible. Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction (PCR) is negative for HCV RNA.
- Pregnancy, lactation, or intention to become pregnant during the study or/and within 1 month after the last dose of olaparib. If the patient can become pregnant, the patient must be on acceptable birth control listed in Appendix 5.
- Participation in a clinical study within 28 days or 5 half-lives of the drug, whichever is longest.
- Patients unable to swallow orally administered medication and/or patients with gastrointestinal disorders likely to interfere with absorption of the study medication.
- Patients with a history of allergy or hypersensitivity to any of the study drugs (including human granulocyte-macrophage colony stimulating factor), yeast-derived products or any constituent of the products.
- Any unresolved toxicity NCI CTCAE Grade ≥ 2 from previous anticancer therapy except for alopecia, vitiligo, and the laboratory values defined in the inclusion criteria. a. Patients with Grade ≥ 2 neuropathy will be evaluated on a case-by-case basis after consultation with the Sponsor. b. Patients with irreversible toxicity not reasonably expected to be exacerbated by treatment with durvalumab may be included only after consultation with the Lead Clinician.
- 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: a. Patients with vitiligo or alopecia. b. Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable on hormone replacement. c. Any chronic skin condition that does not require systemic therapy. d. Patients without active disease in the last 5 years may be included but only after consultation with the Sponsor. e. Patients with celiac disease controlled by diet alone.
- 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 diarrhoea, 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.
- 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). A single ECG ≥ 470 ms is sufficient.
- History of active primary immunodeficiency.
- Active infection including tuberculosis (TB) (clinical evaluation that includes clinical history, physical examination and radiographic findings, and TB testing in line with local practice).
- Receipt of live attenuated vaccine within 30 days prior to the first dose of IMP. Note: Patients, if enrolled, should not receive live vaccine whilst receiving IMP and up to 30 days after the last dose of IMP.
- Has active infection with SARS-CoV-2 (antigen test).
- Patients unable to be regularly followed for any reason (geographic, familiar, social, psychologic, housed in an institution e.g., prison because of a court agreement or administrative order according § 40 Abs. 1 S. 3 Nr. 4 AMG.).
- Patients that are depending on the sponsor/CRO or investigational site as well as on the investigator.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Austria | Not Recruiting | 13 Dec 2021 | 13 |
 Belgium | Not Recruiting | 13 Dec 2021 | 21 |
 Denmark | Not Recruiting | 13 Dec 2021 | 27 |
 Finland | Not Recruiting | 13 Dec 2021 | 27 |
 Germany | Not Recruiting | 13 Dec 2021 | 38 |
 Lithuania | Not Recruiting | 13 Dec 2021 | 10 |
 The Netherlands | Not Recruiting | 13 Dec 2021 | — |
 Norway | Not Recruiting | 13 Dec 2021 | 30 |
 Sweden | Not Recruiting | 13 Dec 2021 | 16 |
| Netherlands | — | — | 6 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Leukine | Test | POWDER FOR SOLUTION FOR INJECTION | INTRADERMAL USE | 75 | 20 | PRD10476811 |
Lynparza 100 mg film-coated tablets | Test | FILM-COATED TABLETS | ORAL USE | 600 | 36 | PRD6163466 |
IMFINZI 50 mg/mL concentrate for solution for infusion. | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS USE | 1500 | 24 | PRD6651398 |
Lynparza 150 mg film-coated tablets | Test | FILM-COATED TABLETS | ORAL USE | 600 | 36 | PRD6152224 |
UV1 | Test | POWDER FOR SOLUTION FOR INJECTION | INTRADERMAL USE | 300 | 20 | PRD2170914 |