| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| recurrent, persistent, or metastatic cervical cancer that have progressed after receiving platinum-based chemotherapy |
|
| E.1.1.1 | Medical condition in easily understood language |
| Cancer that develops in a woman's cervix |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10008231 |
| E.1.2 | Term | Cervical cancer recurrent |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
• To compare the overall survival (OS) in patients with PD-L1 positive tumors randomized to Balstilimab (BAL) vs Investigator’s Choice (IC) chemotherapy
• To compare the OS in all patients randomized to BAL vs IC chemotherapy |
|
| E.2.2 | Secondary objectives of the trial |
• To compare the progression-free survival (PFS) of BAL vs IC chemotherapy in patients with PD-L1 positive tumors randomized to BAL vs IC chemotherapy
• To compare the PFS of BAL vs IC chemotherapy in all patients randomized to BAL vs IC chemotherapy
• To evaluate the objective response rate ORR to BAL and to IC chemotherapy in patients with PD-L1 positive tumors
• To evaluate the ORR to BAL and to IC chemotherapy in all randomized patients |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. ≥ 18 years of age
2. Diagnosis and prior systemic treatment:
a. Has recurrent or metastatic cervical cancer (SCC, AC, or ASC histology), and has experienced disease progression during or after treatment with a standard platinum-based therapy with or without bevacizumab
b. Has received at least 1 prior systemic therapy regimens for recurrent, persistent, and/or metastatic cervical cancer
3. Measurable disease – based on Investigator assessment
a. Radiological evidence of measurable disease on imaging based on RECIST v1.1
Note: Patients must have at least 1 “target lesion” to be used to assess response, as defined by RECIST v1.1. Tumors within a previously irradiated field will be designated as “non-target” lesions unless progression is documented, or a biopsy is obtained to confirm persistence at least 90 days following completion of radiation therapy.
4. Has a life expectancy of at least 3 months and an ECOG performance status of 0 or 1
5. Patients must have sufficient and adequate formalin-fixed tumor tissue sample available that is not older than 3 years; otherwise, a fresh biopsy is required. Archival tissue or fresh biopsy must be from a site not previously irradiated
6. Has adequate organ function as indicated by the following laboratory values:
a. Adequate hematological function defined by absolute neutrophil count ≥ 1.5 × 109/L, platelet count ≥ 100 × 109/L, and stable hemoglobin ≥ 8 g/dL (without transfusions within 1 week before first dose)
b. Adequate hepatic function based by a total bilirubin level ≤ 1.5 × the upper limit of normal (ULN), aspartate aminotransferase (AST) level ≤ 2.5 × ULN, alanine aminotransferase (ALT) level ≤ 2.5 × ULN, alkaline phosphatase (ALP) ≤ 2.5 ×ULN, and albumin ≥ 3.0 mg/dL. In the case of hepatic metastases, < 5 × ULN for AST/ALT and ALP
c. Adequate renal function defined as calculated creatinine clearance > 40 mL/min or a serum creatinine less than 1.5 × ULN, per institutional standards (creatinine clearance should be calculated per institutional standards)
d. Adequate coagulation defined by international normalized ratio or prothrombin time ≤ 1.5 × institutional upper limit of normal (IULN) (unless the patient is receiving anticoagulant therapy); and activated partial thromboplastin time ≤ 1.5 × IULN (unless the patient is receiving anticoagulant therapy) e. Normal thyroid function (thyroid stimulating hormone) whether or not the patient is on supplemental thyroid hormone
7. Has no history of another primary malignancy except for:
a. Malignancy treated with curative intent and with no known active disease ≥ 5 years before the first dose of study drug and of low potential risk for recurrence
b. Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease
c. Adequately treated carcinoma in situ without evidence of disease
d. Adequate coagulation defined by international normalized ratio or prothrombin time ≤ 1.5 × institutional upper limit of normal IULN unless the patient is receiving anticoagulant therapy) and activated partial thromboplastin time ≤ 1.5 × IULN (unless the patient is receiving anticoagulant therapy).
e. Normal thyroid function (thyroid stimulating hormone) whether or not the patient is on supplemental thyroid hormone.
Other protocol defined inclusion criteria apply. |
|
| E.4 | Principal exclusion criteria |
1. Has an inadequate period of time prior to first dose of study treatment that is defined as:
a. Received systemic cytotoxic chemotherapy or biological therapy within 3 weeks before initiation of study treatment
b. Received radiation therapy within 3 weeks before initiation of study treatment, except for palliative bone therapy, which can be received 2 weeks prior to initiation of study treatment
c. Had major surgery within 4 weeks before initiation of study treatment
2. Has received prior therapy with:
a. Any antibody/drug targeting T-cell co-regulatory proteins (immune checkpoints) such as anti–PD-1 and anti–PD-L1 antibodies
3. Has persisting toxicity related to prior therapy of NCI-CTCAE v5.0 Grade ≥ 1 severity with the exceptions noted below:
a. Peripheral neuropathy Grade ≤ 2
b. Alopecia Grade ≤ 2
4. Is expected to require any other form of systemic or localized antineoplastic therapy while on trial (including maintenance therapy with another agent, radiation therapy, and/or surgical resection)
5. Has known severe hypersensitivity reactions to fully human monoclonal antibodies (NCI-CTCAE v5.0 Grade ≥ 3), any history of anaphylaxis, or uncontrolled asthma
6. Is receiving systemic corticosteroid ≤ 7 days prior to the first dose of trial treatment or receiving any other form of systemic immunosuppressive medication (corticosteroid use on trial for management of immune-related adverse events and/or a premedication for IV contrast allergies/reactions is allowed). Patients who are receiving daily corticosteroid replacement therapy are an exception to this rule. Examples of permitted therapy are daily prednisone at doses of 5 to 7.5 mg or equivalent hydrocortisone dose, and steroid therapy administered by topical, intraocular, intranasal, and/or inhalation routes
7. History of central nervous system tumor, metastasis(es), and/or carcinomatous meningitis identified either on the baseline brain imaging obtained during the Screening Period or identified prior to consent
Note: Patients with a history of brain metastases that have been treated may participate provided they show evidence of stable supra-tentorial lesions at screening (based on 2 sets of brain images, performed ≥ 4 weeks apart, and obtained after the brain metastases treatment). In addition, any neurologic symptoms that developed either as a result of the brain metastases or their treatment must have resolved or be minimal and be expected as sequelae from treated lesions. For individuals who received steroids as part of brain metastases treatment, steroids must be discontinued ≥ 7 days prior to the first dose of study drug
8. Has active or history of autoimmune disease that requires systemic treatment within 2 years of the start of study drug (ie, with use of disease-modifying agents, corticosteroids, or immunosuppressive drugs)
Note: Patients with autoimmune conditions requiring hormone replacement therapy or topical treatments are eligible.
9. Has had an allogeneic tissue/solid organ transplant requiring ongoing immunosuppressive treatment
10. Has or had known drug-induced interstitial lung disease, not fully resolved, or has had a history of pneumonitis that has required oral or IV corticosteroids
11. Has an active infection requiring IV systemic treatment
12. Has known history of HIV (HIV 1/2 antibodies)
13. Has known untreated hepatitis B/hepatitis C virus (HBV/HCV) or tuberculosis. Active HBV is defined as a known positive hepatitis B surface antigen result. Active HCV is defined by a known positive hepatitis C antibody result and known quantitative HCV RNA results greater than the lower limits of detection of the assay
14. Has clinically significant (ie, active) cardiovascular disease: cerebral vascular accident/stroke or myocardial infarction within 6 months before enrollment, unstable angina, congestive heart failure (New York Heart Association class ≥ II), or serious uncontrolled cardiac arrhythmia requiring medication.
Other protocol defined exclusion criteria apply |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The OS time, defined as time from randomization to death from any cause. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
For patients who are still alive at time of data cutoff for trial analysis or who are lost to follow-up, survival will be censored at the last recorded date that the patient is known to be alive as of the cutoff date for analysis.
Time until observing 234 OS events but no later than 36 months after enrollment of the last patient |
|
| E.5.2 | Secondary end point(s) |
• PFS duration, defined as time from randomization until death or disease per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1; Eisenhauer 2009) and Investigator assessment
• ORR per RECIST v1.1, per Investigator, defined as the binomial proportion of confirmed complete response (CR) or partial response (PR) per RECIST v1.1 criteria |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Time until observing 234 OS events but no later than 36 months after enrollment of the last patient |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 109 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Armenia |
| Australia |
| Brazil |
| Canada |
| Chile |
| Colombia |
| Georgia |
| India |
| Israel |
| Korea, Republic of |
| Malaysia |
| Peru |
| Russian Federation |
| Singapore |
| Taiwan |
| Turkey |
| Ukraine |
| United States |
| Austria |
| Bulgaria |
| Croatia |
| Denmark |
| Estonia |
| Finland |
| France |
| Germany |
| Hungary |
| Italy |
| Latvia |
| Lithuania |
| Netherlands |
| Poland |
| Portugal |
| Spain |
| Czechia |
| Argentina |
| Greece |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| If the trial is not terminated prematurely, the end of the trial is defined as approximately 30 months after the last patient has received the last planned dose of study drug. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 11 |
| E.8.9.1 | In the Member State concerned days | 27 |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| E.8.9.2 | In all countries concerned by the trial months | 4 |
| E.8.9.2 | In all countries concerned by the trial days | 8 |
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