Chemotherapy plus Paclitaxel with Bevacizumab and Atezolizumab versus Chemotherapy plus Paclitaxel and Bevacizumab in Carcinoma of the Cervix

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Grupo Espanol De Investigacion En Cancer De Ovario

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

2 Oct 2018 → 31 Aug 2025

Decision date (initial)

2024-11-22

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

External identifiers

EU CT number

2024-514179-17-00

EudraCT number

2018-000367-83

ClinicalTrials.gov

NCT03556839

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacodynamic, Pharmacokinetic, Efficacy, Safety

- To determine the progression free survival (PFS) of combining atezolizumab to chemotherapy (cisplatin or carboplatin/paclitaxel [CP]) and bevacizumab compared to CP and bevacizumab.
- To determine whether the addition of atezolizumab to chemotherapy (CP) plus bevacizumab improves overall survival (OS) compared to CP plus bevacizumab.

Secondary objectives 6

1. Objective Response Rate (ORR)
2. Safety and tolerability
3. Duration of response (DOR)
4. Time from randomization to first subsequent therapy or death (TFST)
5. Time from randomization to second progression (PFS2)
6. Patient-reported outcomes (PROs) of function and health related quality of life (HR-QOL)

Conditions and MedDRA coding

Metastatic (stage IVB), Persistent, or Recurrent Carcinoma of the Cervix

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 16

1. Female patients must be ≥18 years of age
2. Signed informed consent before any study-specific procedure
3. Able (in the investigator´s judgment) to comply with the study protocol
4. GOG/Eastern Cooperative Oncology Group (ECOG) performance status of 0-1
5. Life expectancy ≥3 months
6. Histologically- or cytologically-confirmed diagnosis of metastatic (stage IVB), persistent, or recurrent cervical cancer (histologies other than squamous cell, adenocarcinoma, or adenosquamous will be excluded) not amenable for curative treatment with surgery and/or radiation therapy. The inclusion of patients with adenocarcinoma histology will be capped to 20% of the whole study population
7. No prior systemic anti-cancer therapy for metastatic or recurrent disease. - Concurrent chemo-radiotherapy treatment with curative intent or adjuvant chemo-radiotherapy must have been completed ≥3 months (90 days) prior to enrollment. - Palliative radiation therapy (e.g., for pain or bleeding) 6 weeks prior enrollment is allowed as long as this does not affect measurable disease and patients are recovered from its symptoms.
8. Measureable disease by RECIST v1.1 criteria: Patients must have at least 1 "target lesion" to be used to assess response on this protocol as defined by RECIST v1.1. If the only target lesion is limited to the radiation field, a biopsy is required to confirm malignancy.
9. A tumor specimen is mandatory at study entry. This may be an archival biopsy or, in its absence, a tumor biopsy obtained within 3 months of randomization from a non-irradiated lesion. Paired recent biopsies at baseline (lesion not previously irradiated; within 3 months of randomization) and at progression disease will not be mandatory, nevertheless they are encouraged as long as these are feasible
10. Adequate organ function: o Hemoglobin ≥9 g/dL (transfusion and / or erythropoietin permitted) o ANC ≥1.5 × 109/L o Lymphocyte count ≥0.5 × 109/L o Platelet count ≥100 x 109/L
11. Adequate liver function: o Serum albumin ≥2.5 g/dL o Total serum bilirubin ≤1.5 ×ULN o AST and ALT ≤2.5 × ULN or ≤5 × ULN if tumor involvement (liver) is present
12. Adequate renal function: o Patients with serum creatinine <1.5 × ULN o Urine dipstick for proteinuria <2+. Patients discovered to have 2+ proteinuria on dipstick urinalysis at baseline should undergo a 24-hour urine collection and must demonstrate <1 g of protein in 24 hours or urine protein/creatinine (UPC) ratio ≤ 1.0
13. Adequate coagulation: o Blood coagulation parameters (PTT, PT/INR): PT such that international normalized ratio (INR) is ≤1.5 (or an in-range INR, usually between 2 and 3, if a patient is on a stable dose of therapeutic warfarin for management of venous thrombosis including pulmonary thromboembolus) and a PTT <1.5 × ULN.
14. Negative Test Results for Hepatitis
15. Toxicities related to previous treatments must be recovered to < grade 2 (with the exception of alopecia).
16. Female participants must be postmenopausal (≥ 12 months of nontherapyinduced amenorrhoea) or surgically sterile (absence of ovaries and/or uterus, or who received therapeutic radiation to the pelvis) or otherwise have a negative serum pregnancy test within 7 days of the first study treatment and agree to abstain from heterosexual intercourse or use single or combined contraceptive methods that result in a failure rate of <1% per year during the whole treatment period of the study and for at least 5 months (if the last study dose contained atezolizumab) or 6 months (if the last study dose contained bevacizumab) after the last dose of study treatment.

Exclusion criteria 46

1. Disease that is suitable for local therapy administered with curative intent
2. Prior radiotherapy delivered using cobalt.
3. Patients with Stage IVA not amendable to concurrent chemo-radiation as primary treatment.
4. Ongoing disease involving the bladder or rectum at screening/baseline
5. Evidence of abdominal free air.
6. Bilateral hydronephrosis.
7. Patients previously treated with chemotherapy
8. Prior treatment with any anti-VEGF drug
9. Patients with a concomitant malignancy other than non-melanoma skin cancer
10. Known brain metastases or spinal cord compression
11. History or evidence, following a neurological examination unless properly treated with standard medical treatment.
12. Patients with serious non-healing wound, ulcer, or bone fracture.
13. Acute intestinal obstruction or sub-occlusion episode in the last 6 months.
14. Active GI bleeding or GI ulcer
15. History of Crohn's disease or inflammatory bowel disease
16. Prior bowel resection ≤6 weeks preceding first study dose
17. History of diverticulitis requiring medical intervention.
18. NCI CTCAE (version 5.0) grade ≥2 enteritis.
19. Major surgical procedure, open biopsy or significant traumatic injury within 28 days prior to D1C1.
20. Core biopsy or other minor surgical procedure, excluding placement of a vascular access device, within 7 days prior to D1C1.
21. Patients with active bleeding or pathologic conditions that carry high risk of bleeding
22. Current or recent chronic daily treatment with aspirin, clopidogrel, or current or recent use of therapeutic oral or parenteral anticoagulants or thrombolytic agents for therapeutic purposes.
23. Patients with pre-existing Grade 2 or greater peripheral neuropathy.
24. History of any grade ≥3 venous thromboembolic event (VTE).
25. Patients with clinically significant cardiovascular disease.
26. Left ventricular ejection fraction defined by MUGA/ECHO below the institutional lower limit of normal
27. Uncontrolled tumor-related pain.
28. Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures
29. Uncontrolled hypercalcemia or symptomatic hypercalcemia requiring continued use of bisphosphonate therapy or denosumab.
30. History of autoimmune disease.
31. History of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis on screening chest CT scan. History of radiation pneumonitis in the radiation field is permitted.
32. Active tuberculosis
33. Severe infections within 4 weeks prior to Cycle 1, Day 1, including but not limited to hospitalization for complications of infection, bacteremia, or severe pneumonia.
34. Signs or symptoms of infection within 2 weeks prior to Cycle 1, Day 1
35. Received therapeutic oral or IV antibiotics within 2 weeks prior to Cycle 1,Day 1.
36. Known human immunodeficiency virus (HIV).
37. Administration of a live, attenuated vaccine within 4 weeks before Cycle 1, Day 1 or anticipation that such a live attenuated vaccine will be required during the study.
38. Any other diseases, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or that may affect the interpretation of the results or render the patient at high risk from treatment complications.
39. Treatment with systemic immunostimulatory agents within 6 weeks or 5 half-lives of the drug, whichever is shorter, prior to Cycle 1, Day 1.
40. Treatment with systemic immunosuppressive medications within 2 weeks prior to Cycle 1, Day 1. The use of corticosteroids is allowed as premedication for paclitaxelbased regimen
41. Currently participating or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks prior to the first dose of study treatment.
42. Prior anti-cancer monoclonal antibody (mAb), prior chemotherapy, targeted small molecule therapy as first line treatment for the treatment of metastatic or recurrent cervical cancer.
43. Women that are breastfeeding or pregnant
44. Known hypersensitivity to bevacizumab, atezolizumab or any of theirs excipients (including Cremophor).
45. No medical or psychiatric illness that may impede the performance of a systemic or surgical treatment
46. Demonstration of any other neurological or metabolic dysfunction

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. Progression free survival (PFS)
2. Overall Survival (OS)

Secondary endpoints 11

1. Objective Response Rate (ORR)
2. Duration of response (DOR)
3. Frequency and severity of adverse events
4. Time from randomization to first subsequent therapy or death (TFST)
5. Time from randomization to second progression (PFS2) based on radiologic assessment, start of a new line of therapy, symptomatic deterioration or death
6. Mean and mean changes from baseline score in patient function (role, physical) and GHS/HRQoL.
7. Proportion of patients reporting each response option
8. Utility scores of the EQ-5D-5L questionnaire.
9. Relationship between tumour immune-related or disease type-related biomarkers.
10. Relationship between certain exploratory biomarkers
11. Relationship between ATB use within 2 months before and 1 month after the first study administration with atezolizumab efficacy as measured by PFS and OS.

Investigational products

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

Test 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Grupo Espanol De Investigacion En Cancer De Ovario

Sponsor organisation

Grupo Espanol De Investigacion En Cancer De Ovario

Address

Calle De Santa Engracia 151 Planta 5ª Oficina 2

City

Madrid

Postcode

28003

Country

Spain

Scientific contact point

Organisation

Grupo Espanol De Investigacion En Cancer De Ovario

Contact name

APICES SOLUCIONES S.L, Clinical Operations Department

Public contact point

Organisation

Grupo Espanol De Investigacion En Cancer De Ovario

Contact name

APICES SOLUCIONES S.L, Clinical Operations Department

Third parties 1

Locations

6 EU/EEA countries · 60 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 51 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

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