The assessment of bevacizumab dose equivalence in ovarian cancer

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Uniwersytet Medyczny W Lublinie

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Female

Therapeutic area

Not possible to specify

Decision date (initial)

2024-07-15

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

Medical Research Agency, 1A Stanisława Moniuszki Street, 00-014 Warszawa

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Efficacy, Dose response, Therapy

The primary objective of the study is to verify the hypothesis that there is no difference in survival to progression for patients enrolled in the standard 15mg and low 7.5 mg dose arms of bevacizumab as part of their treatment of ovarian cancer.

Secondary objectives 1

1. The secondary objective is to assess the net clinical effect of the efficacy endpoints in a broken down into individual events (death, disease progression, need for subsequent therapy) in relation to safety defined as the incidence of adverse events(AE/SAE/AESI).

Conditions and MedDRA coding

Patients with ovarian cancer, fallopian tube cancer, peritoneal carcinoma

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 21

1. Age ≥ 18 years.
2. Performance of a test assessing the presence of pathogenic mutations in BRCA1/2 genes using Next-Generation Sequencing (NGS) technique in tissue, and conducting a test assessing Homologous Recombination Deficiency (HRD) status.
3. Previous disqualification from primary cytoreductive surgery and qualification for neoadjuvant chemotherapy due to ovarian cancer.
4. General performance status at levels 0-1 according to ECOG classification.
5. Blood morphology results with smear: a. Platelet count greater than or equal to 1.5 x 10^5/mm^3, b. Leukocyte count greater than or equal to 3.0 x 10^9/L, c. Absolute neutrophil count greater than or equal to 1.5 x 10^9/L, d. Hemoglobin concentration greater than or equal to 10.0 g/dL.
6. Coagulation indicators: e. Activated Partial Thromboplastin Time (APTT) below 1.5 times the upper limit of normal; f. Prothrombin Time (PT) or International Normalized Ratio (INR) below 1.5 times the upper limit of normal.
7. Complete or partial response to neoadjuvant chemotherapy.
8. Previous delayed cytoreductive surgery after neoadjuvant chemotherapy, regardless of the presence and size of residual disease.
9. Receiving 3 cycles of platinum and paclitaxel-based neoadjuvant chemotherapy with bevacizumab at a dose of 7.5 mg/kg b.w.
10. Cytoreductive surgery performed within 8 weeks before study inclusion.
11. Availability of the formalin-fixed, paraffin-embedded (FFPE) primary tumor sample.
12. Liver and kidney function indicators: g. Total bilirubin concentration not exceeding 1.5 times the upper limit of normal (except for patients with Gilbert's syndrome); h. Serum transaminase activity (alanine and aspartate) not exceeding 2.5 times the upper limit of normal (5 times in patients with liver metastases); i. Creatinine concentration not exceeding 1.5 times the upper limit of normal.
13. Commitment from reproductive-capable individuals to abstain from heterosexual intercourse or use two effective methods of contraception starting 4 weeks before the beginning of treatment, during therapy, during dose interruptions, and for 6 months after the last dose of the drug.
14. Normal blood pressure or controlled hypertension (systolic BP ≤ 140 mmHg and/or diastolic BP ≤ 90 mmHg).
15. Postmenopausal status or exclusion of pregnancy in reproductive-age women before the first dose of the investigational drug.
16. No contraindications to the use of bevacizumab, carboplatin, paclitaxel according to the Summary of Product Characteristics (SPC).
17. No contraindications to the use of olaparib according to the Summary of Product Characteristics (SPC) (applies to patients with BRCA1/2 mutations and/or HRD presence).
18. Obtaining an informed, voluntary consent form from the patient to participate in the study.
19. Capability and willingness to comply with the study protocol requirements.
20. Histological diagnosis of advanced (stage III-IV according to FIGO) high-grade ovarian cancer (high-grade, G2 or G3), fallopian tube cancer, or primary peritoneal cancer.
21. Refraining from ova donation and cryopreservation for an appropriate period during study treatment and for 6 months after the study, according to the study results classes on contraception CTFG 1.1.

Exclusion criteria 19

1. Another malignant tumor occurring synchronously or treated within the last 3 years. Exceptions include low-potential metastasis-prone tumors such as in situ breast, cervical, or skin cancers.
2. Occurrence of a neoadjuvant therapy-related adverse event grade ≥ 3 according to CTCAE v.5.0, which has not been resolved or reduced to grade 1 before randomization.
3. History of a clinically significant cardiovascular disease, including: a. Hypertension or hypertensive encephalopathy, defined according to ESH 2023 guidelines; b. Previous acute coronary syndrome within ≤ 6 months of randomization; under 2023 ESC guidelines; c. Congestive heart failure (CHF) degree ≥ 3 NYHA (New York Heart Association); d. Poorly controlled heart rhythm despite treatment (patients with well-controlled, persistent atrial fibrillation are eligible) or any clinically significant abnormalities in resting ECG (including QTc interval >450 ms) as assessed by the investigator; e. Peripheral vascular disease degree ≥ 3, according to Rutherford classification; f. Previous cerebrovascular accident, transient ischemic attack, or subarachnoid hemorrhage within 6 months before randomization; g. History or evidence of existing bleeding disorders within 6 months before randomization; h. Evidence of bleeding disorder or significant coagulopathy in the investigator's opinion preventing participation in the study.
4. History or clinical suspicion of brain metastases or spinal cord compression.
5. Central nervous system (CNS) disease unless adequately treated with standard medical therapy (e.g., uncontrolled seizures).
6. Significant injury or major surgery within 4 weeks before randomization (excluding cytoreductive surgery in the treatment of ovarian, fallopian tube, or primary peritoneal cancer);
7. Non-healing wound, active ulcer, or bone fracture. Patients with granulating wounds healing secondarily without signs of infection may be included in the study.
8. History of abdominal fistula or gastrointestinal perforation related to VEGF inhibitors or active gastrointestinal bleeding within 6 months before the first investigational treatment.
9. Active gastric or duodenal ulcer in the investigator's assessment.
10. Current signs of clinically significant bowel obstruction, including sub-occlusive disease, related to the underlying disease.
11. Inability to swallow orally administrated drug and patients with gastrointestinal disorders that may interfere with the absorption of the investigational drug.
12. Use of anticoagulant or antiplatelet medications (excluding use in prophylactic doses).
13. Known hypersensitivity to bevacizumab, olaparib, carboplatin, paclitaxel, or any excipient.
14. Hypersensitivity to products derived from Chinese hamster ovary cells or other recombinant human or humanized antibodies.
15. Evidence of any other disease, metabolic dysfunction, physical or laboratory examination result giving reasonable suspicion of a condition or disease that constitutes a contraindication to the use of the investigational drug or exposes the patient to a high risk of complications associated with treatment in the investigator's opinion.
16. Pregnancy or breastfeeding.
17. Concurrent participation in another clinical trial (patients previously participating in clinical trials may be included, provided that three times the half-life of the investigational drug has elapsed from the last dose to randomization).
18. Clinically active, uncontrolled infection such as HBV, HCV, HIV.
19. Any situation that, in the investigator's opinion, may prevent the conduct of the study according to the protocol or to provide of written consent, e.g., alcohol, drug or substance abuse, addiction.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. Objective Response Rate (ORR) to treatment, defined as the proportion of patients with a complete or partial response to treatment according to response evaluation criteria in solid tumors (RECIST v.1.1) within 4 weeks after the completion of the adjuvant treatment phase.
2. Progression-free survival (PFS), defined as the time from randomization to disease progression/recurrence according to response evaluation criteria in solid tumors (RECIST v.1.1) or all-cause death, whichever comes first.

Secondary endpoints 7

1. Frequency of adverse events (AE).
2. Frequency of serious adverse events (SAE).
3. Frequency of adverse events of special interest (AESI).
4. Death from any cause
5. ORR based on best overall response (BOR) over the entire treatment period according to RECIST v.1.1
6. Time from start of first-line chemotherapy to start of first subsequent therapy (TFST)
7. An analysis of the study participant's quality of life will be made on the basis of: - the standardised quality of life questionnaires QLQ-C30 and QLQ-OV28 of the European Organisation for Research and Treatment of Cancer

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Auxiliary 4

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Uniwersytet Medyczny W Lublinie

Sponsor organisation

Uniwersytet Medyczny W Lublinie

Address

Ul. Aleje Raclawickie 1

City

Lublin

Postcode

20-059

Country

Poland

Scientific contact point

Organisation

Uniwersytet Medyczny W Lublinie

Contact name

Marcin Bobiński

Public contact point

Organisation

Uniwersytet Medyczny W Lublinie

Contact name

Marcin Bobiński

Third parties 1

Locations

1 EU/EEA country · 11 investigational sites

By country

Investigational sites

Application history

1 submissions — initial application plus substantial / non-substantial modifications