A Phase 2b, Randomized, Double-blind Study Comparing Tremelimumab to Placebo in Second- or Third-line Treatment of Subjects with Unresectable Pleural or Peritoneal Malignant Mesothelioma

Summary

This is a Phase 2b, randomized, double-blind, parallel-group study. Subjects with unresectable pleural or peritoneal malignant mesothelioma will be randomized in a 2:1 ratio to receive either tremelimumab or placebo. Randomization will be stratified by eoRTC status (low-risk vs high-risk; see appendix 3), line of therapy (second vs third), and anatomical site (pleural vs peritoneal). This study plans to use the eoRTC status to stratify subjects into high or low
risk groups in order to ensure balanced randomization to the different treatment groups. For subjects in whom pemetrexed was contraindicated or not tolerated or not an approved therapy (eg, peritoneal mesothelioma), prior therapy with a first-line platinum-based regimen is required. Though the number of subjects not receiving prior pemetrexed is expected to be small, the proportion of such subjects enrolled in the study will be capped at 20%. approximately 564 subjects will be enrolled at approximately 180 study centers in multiple countries.

The study consists of a screening period, a treatment period, and a 90-day follow-up period. The treatment period will consist of 6 doses Q4W followed by doses Q12W until PD or withdrawal of consent.

The tremelimumab dose employed in this study will be 10 mg/kg Q4W for the first 6 months, after which tremelimumab will be given Q12W at the same dose, as long as the subjects continues to derive clinical benefit. The selected dose and schedule is informed by safety and efficacy data on tremelimumab, and by data showing a relationship between exposure and survival in the advanced melanoma studies with tremelimumab.

Primary endpoint:
The primary endpoint is oS which is defined as the time from randomization until death due to any cause. The primary analysis of oS will be performed after 124 deaths have occurred among the approximately 180 subjects randomized. For subjects who are alive at the time of the primary analysis or lost to follow-up, oS will be censored on the last date when subjects are known to be alive. The distribution of oS times will be estimated using the Kaplan-Meier method (Kaplan and Meier, 1958). The primary comparison of the 2 treatment arms will be
performed by a stratified log-rank test with 3 stratification factors specified in Section 4.3. in addition, the hazard ratio (HR) of tremelimumab vs placebo and its 80% and 95% confidence intervals will be estimated using a stratified Cox regression model with ties handled by the efron method (efron, 1977). The primary analysis will be based on the iTT Population. Sensitivity analyses will be conducted based on the PP population.

Secondary endpoints:
efficacy:
The secondary efficacy endpoints include PRos as well as durable DCR, PFS, oRR, and
duration of response, based on modified ReCiST criteria for pleural mesothelioma and
ReCiST criteria v 1.1 for peritoneal mesothelioma. The analysis of these secondary
endpoints will be based on investigator-determined response data.

Participant Eligibility

Subjects must meet all of the following criteria:
1) Histologically and/or cytologically confirmed pleural or peritoneal malignant
mesothelioma;
2) Disease not amenable to curative surgery;
3) Age 18 and over at the time of consent;
4) ECOG Performance status 0-1;
5) Previous receipt of 1-2 prior systemic chemotherapies that included first-line
pemetrexed (or anti-folate)-based regimen in combination with platinum agent. For
subjects in whom pemetrexed was contraindicated or not tolerated or not an approved
therapy (eg, peritoneal mesothelioma), prior therapy with a first-line platinum-based
regimen is required;
6) Recovered from all toxicities associated with prior treatment, to acceptable baseline
status, or a National Cancer Institute Common Terminology Criteria for Adverse
Events (NCI CTCAE) Grade of 0 or 1, except for toxicities not considered a safety
risk, such as alopecia or vitiligo;
7) Measurable disease, defined as at least 1 lesion (measurable) that can be accurately
assessed at baseline by computed tomography (CT) or magnetic resonance imaging
(MRI) and is suitable for repeated assessment (modified Response Evaluation Criteria
in Solid Tumors [RECIST] for pleural mesothelioma or RECIST v1.1 for peritoneal
mesothelioma);
8) Adequate bone marrow, hepatic, and renal function determined within 14 days prior
to randomization defined as:
a) Platelet count >= 75,000/mm3;
b) Absolute neutrophil count >= 1,000/mm3;
c) Hemoglobin >= 9 g/dL;
d) Total bilirubin <= 1.5 x ULN (upper limit of normal) except subjects with
documented Gilbert[Single Quote]s syndrome (> 5 x ULN) or liver metastasis, who must have a
baseline total bilirubin <= 3.0 mg/dL;
e) Aspartate transaminase (AST) and alanine transaminase (ALT) <= 3 x ULN
(<= 5 x ULN if documented liver metastasis are present);
f) Serum creatinine <= 2.0 mg/dL or calculated creatinine clearance >= 50 mL/min as
determined by the Cockcroft-Gault equation;
9) Negative screening test results for human immunodeficiency virus (HIV), hepatitis A,
B and C. If positive results are not indicative of true active or chronic infection, the subjects can enter the study after discussion and agreement between the investigator
and the contract research organization (CRO) medical monitor;
10) Written informed consent and any locally required authorization (eg, HIPAA in the
USA, EU Data Privacy Directive authorization in the EU) obtained from the
subject/legal representative prior to performing any protocol-related procedures,
including screening evaluations;
11) Females of childbearing potential who are sexually active with a nonsterilized male
partner must use a highly effective method of contraception for 28 days prior to the
first dose of investigational product, and must agree to continue using such
precautions for 6 months after the final dose of investigational product; cessation of
contraception after this point should be discussed with a responsible physician.
Periodic abstinence, the rhythm method, and the withdrawal method are not
acceptable methods of contraception. They must also refrain from egg cell donation
for 6 months after the final dose of investigational product;

* Females of childbearing potential are defined as those who are not surgically
sterile (ie, bilateral tubal ligation, bilateral oophorectomy, or complete
hysterectomy) or postmenopausal (defined as 12 months with no menses
without an alternative medical cause);

* A highly effective method of contraception is defined as one that results in a
low failure rate (ie, less than 1% per year) when used consistently
and correctly. The acceptable methods of contraception are described in
Table 4.2.1-1;
12) Nonsterilized males who are sexually active with a female partner of childbearing
potential must use a highly effective method of contraception (see Table 4.2.1-1) from
Day 1 through 90 post last dose. In addition, they must refrain from sperm donation
for 90 days after the final dose of investigational product;