IRB Study Number 24-482
Status Recruiting
Institute Taussig Cancer Institute
Description
Primary Objectives
To demonstrate the superiority of volrustomig in combination with carboplatin plus pemetrexed relative to investigator’s choice of nivolumab in combination with ipilimumab or platinum plus pemetrexed by assessment of OS in PM participants with epithelioid histology.
Secondary Objectives
To demonstrate the effectiveness of volrustomig in combination with carboplatin plus pemetrexed relative to investigator’s choice of nivolumab in combination with ipilimumab or platinum plus pemetrexed by assessment of OS in all randomized participants.
To demonstrate effectiveness of volrustomig in combination with carboplatin plus pemetrexed relative to investigator’s choice of nivolumab in combination with ipilimumab or platinum plus pemetrexed by assessment of PFS.
Inclusion Criteria
Age
1 Participant must be ≥ 18 years at the time of screening.
Type of Participant and Disease Characteristics
2 All races, genders, and ethnic groups are eligible for this study.
3 Histologically proven diagnosis of PM with known histology (epithelioid vs. nonepithelioid).
4 Advanced unresectable disease that cannot be treated with surgery with curative intent (with or without chemotherapy).
5 WHO/ECOG performance status of 0 or 1 with no deterioration (that is, ECOG PS > 1) over the previous 2 weeks prior to day of first dosing.
6 Life expectancy ≥ 12 weeks.
7 Provision of existing (leftover) tumor sample obtained within 6 months prior to screening is required, if available.
8 Measurable disease, per investigator assessment, defined as:
(a) Mesothelioma tumor thickness perpendicular to the chest wall or mediastinum, that can be measured in up to 2 positions at 3 separate levels on transverse cuts of CT scan (cuts must be at least 10 mm apart), for a total of up to 6 measurements. Each single tumor measurement must be at least 7 mm to qualify as measurable disease and contribute to the sum that defines the pleural measurement as per mRECIST 1.1 criteria. See Appendix F.
(b) Non-pleural metastatic target lesions measured uni-dimensionally as per RECIST 1.1 criteria. See Appendix F.
(c) Patients who present without pleural lesions that can be considered measurable, but with metastatic lesions (non-pleural) meeting criteria for target lesion by RECIST 1.1 criteria may be considered for inclusion, based upon the investigator’s judgment.
9 Adequate organ and bone marrow function (in the absence of transfusions or growth factor support within 14 days prior to enrollment) as defined below in Table 11. (See protocol)
Weight
10 Body weight > 35 kg.
Sex and Contraceptive/Barrier Requirements
11 Male and/or female.
Contraceptive use by males or females should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies; see below and Appendix G for further details.
(a) Male participants: Non-sterilized male participants who are sexually active with a female partner of childbearing potential must use a condom with spermicide from enrolment until at least 90 days after the last dose of volrustomig, and 180 days after the last dose of pemetrexed or carboplatin (Note: Male condoms are not reliable as a sole contraception method). IT IS STRONGLY RECOMMENDED THAT female partners of a male participant also use at least one highly effective method of contraception throughout this period. In addition, male participants must refrain from fathering a child or donating sperm from enrolment, throughout the study, and until at least 90 days after the last dose of volrustomig, and 180 days or per local prescribing information after the last dose of all other study treatments.
(b) Female participants:
– Females receiving HRT and whose menopausal status is in doubt will be required to use one of the contraception methods outlined for females of childbearing potential if they wish to continue using HRT during the study. Otherwise, HRT must be discontinued to allow confirmation of post-menopausal status prior to study enrolment.
– If sexually active with a non-sterilized male partner, female participants of childbearing potential must use at least one highly effective method of birth control from enrolment, throughout the study, and until at least 90 days after the last dose of volrustomig, and 180 days or per local prescribing information after the last dose of all other study treatments.
– All females of childbearing potential must have a negative serum pregnancy test result at Visit 1 (ie, during the screening period).
Informed Consent
12 Capable of giving signed informed consent as described in 10 which includes compliance with the requirements and restrictions listed in the ICF and in this CSP.
13 Provision of signed and dated written Optional Genetic Research Information informed consent prior to collection of samples for optional genetic research that supports the Genomic Initiative (see Appendix D).
Other Inclusion Criteria
14 Prior palliative radiotherapy is permitted, but at least 14 days must elapse prior to first dose and all signs of toxicity must be resolved.
Exclusion Criteria
Medical Conditions
As judged by the investigator, any condition that would interfere with evaluation of the investigational product or interpretation of participant safety or study results.
History of another primary malignancy except for:
(a) Malignancy treated with curative intent and adequate follow-up with no known active disease or have not required active treatment within the past 2 years before the first dose of study intervention and of low potential risk for recurrence.
(b) Adequately treated nonmelanoma skin cancer or lentigo maligna without evidence of disease.
(c) Adequately treated carcinoma in situ, including Ta bladder tumors, without evidence of disease. Cancer participants with incidental histologic findings of prostate cancer that, in the opinion of the investigator, is not deemed to require active therapy (eg, incidental prostate cancer identified following cystoprostatectomy that is tumor/node/metastasis stage ≤ pT2N0) may be enrolled, pending discussion and approval by the investigator.
Active or prior documented autoimmune or inflammatory disorders including inflammatory bowel disease (eg, colitis or Crohn's disease), diverticulitis (with the exception of diverticulosis), celiac disease, systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome (granulomatosis with polyangiitis), Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, pneumonitis (past medical history of ILD, drug-induced ILD, or radiation pneumonitis requiring steroid treatment, or any evidence of clinically active ILD), etc. The following are exceptions to this criterion:
(a) Participants with vitiligo or alopecia.
(b) Participants with hypothyroidism (eg, following Hashimoto syndrome) stable on hormone replacement.
(c) Any chronic skin condition that does not require systemic therapy.
(d) Participants without active disease in the last 5 years prior to enrolment may be included.
(e) Participants with celiac disease controlled by diet alone.
History of active primary immunodeficiency.
Untreated or progressive CNS metastatic disease, any leptomeningeal disease, or cord compression. Participants with suspected brain metastases at screening should have a CT/MRI of the brain prior to study entry. The following participants can be included:
- Participants previously treated with radiation or surgical resection within 3 months prior to first dose of investigational products for CNS metastases who are asymptomatic, and clinically stable who do not require corticosteroids for at least 14 days prior to the first dose of investigational product.
As judged by the investigator, any evidence of diseases (such as severe or uncontrolled systemic diseases, including, but not limited to, ongoing or active infection, cardiomyopathy of any etiology, symptomatic congestive heart failure [as defined by New York Heart Association class > 2], uncontrolled hypertension, unstable angina pectoris, history of myocardial infarction within the past 12 months, ILD, serious chronic gastrointestinal conditions associated with diarrhea, or psychiatric illness/social situations, and active bleeding diseases) and/or history of organ transplant or allogeneic stem cell transplant, which, in the investigator’s opinion, makes it undesirable for the participant to participate in the study or that would jeopardize compliance with the protocol.
Evidence of the following infections:
(a) Active infection including tuberculosis (clinical evaluation that includes clinical history, physical examination, and radiographic findings and tuberculosis testing in line with local practice),
(b) HIV infection that is not well controlled. All of the following criteria are required to define an HIV infection that is well controlled: undetectable viral RNA load for 6 months, CD4+ count of > 500 cells/μL, stable for at least 6 months on the same anti-HIV medications, and no history of AIDS (either CD+T cell count < 200 cells/μL and/or AIDS-defining opportunistic infection).
(c) or active or uncontrolled hepatitis B (HBV) or hepatitis C (HCV); refer to Section 1.3 and Section 8.3.4 for screening tests. Participants are eligible if they:
Have controlled hepatitis C viral load defined as undetectable hepatitis C RNA by PCR either spontaneously or in response to a successful prior course of anti-hepatitis C therapy
Have received HBV vaccination with only anti-HBs positivity and no clinical signs of hepatitis
Are HBsAg- and anti-HBc+ (ie, those who have cleared HBV after infection) and meet conditions i-iii below:
Are HBsAg+ with chronic HBV infection (lasting 6 months or longer) and meet conditions i, ii and iii below:
i. HBV DNA viral load < 100 IU/mL
ii. Have normal transaminase values, or, if liver metastases are present, abnormal transaminases, with a result of AST/ALT < 3 × ULN, which are not attributable to HBV infection
iii. Start or maintain antiviral treatment if clinically indicated as per the investigator
(d) or active hepatitis A
Participant meets one or more of the following:
Resting corrected QT interval >480 ms, obtained from electrocardiograms (ECGs) performed at screening.
History of QT prolongation associated with other medications that required discontinuation of that medication.
Congenital long QT syndrome, family history of long QT syndrome, or unexplained sudden death under 40 years of age in first-degree relatives.
History of arrhythmia (multifocal premature ventricular contractions, bigeminy, trigeminy, ventricular tachycardia), which is symptomatic or requires treatment (CTCAE Grade 3), symptomatic or uncontrolled atrial fibrillation despite treatment, or asymptomatic sustained ventricular tachycardia. Participants with atrial fibrillation controlled by medication or arrhythmias controlled by pacemakers may be permitted based on the investigator judgment with cardiologist consultation recommended.
Prior/Concomitant Therapy
Prior therapy for PM, including chemotherapy (adjuvant, neoadjuvant), radical pleuropneumonectomy with or without intensity modulated radiotherapy (excluding debulking surgery), and non-palliative radiation therapy, intraoperative or intracavitary chemotherapy for PM.
Current or prior use of immunosuppressive medication within 14 days before the first dose of investigational product; the following are exceptions to this criterion:
(a) Intranasal, inhaled, topical steroids, or local steroid injections (eg, intraarticular injection).
(b) Steroids as premedication for hypersensitivity reactions (eg, CT scan premedication) or a single dose for palliative purpose (eg, pain control).
Prior exposure to immune-mediated therapy including, but not limited to, other anti-CTLA-4, anti-PD-1, anti-PD-L1, and anti-PD-L2 antibodies, excluding therapeutic anticancer vaccines.
Radiotherapy treatment with a wide field of radiation or to more than 30% of the bone marrow within 4 weeks, prior to the first dose of study intervention.
Major surgery within 4 weeks prior to the first dose of study intervention or still recovering from prior surgery. Note: Local surgery of isolated lesions for palliative intent is acceptable.
Receipt of live attenuated vaccine within 30 days prior to the first dose of investigational product. Note: Participants, if enrolled, should not receive live vaccine while receiving investigational product and up to 30 days after the last dose of volrustomig, and according to local prescribing information for all other study treatments.
Any concurrent chemotherapy, radiotherapy, investigational, biologic, or hormonal therapy for cancer treatment. Concurrent use of hormonal therapy for noncancer-related conditions (eg, insulin for diabetes and HRT) is acceptable. NOTE: Local treatment of isolated lesions for palliative intent is acceptable (eg, metastasis treated by local surgery or radiotherapy).
Any concomitant medication known to be associated with Torsades de pointes.
History of anaphylaxis to any biologic therapy or vaccine.
Prior/Concurrent Clinical Study Experience
Concurrent enrolment in another clinical study, unless it is an observational (non-interventional) clinical study or the follow-up period of an interventional study.
Participants with a known allergy or hypersensitivity to investigational product(s), or any excipients of the investigational product(s).
Medical contraindication to platinum pemetrexed (carboplatin or cisplatin)-based chemotherapy.
Previous enrolment or randomization in the present study.
Diagnostic Assessments
Primitive peritoneal, pericardial, testis or tunica vaginalis mesothelioma.
Undetermined histology of epithelioid vs. non-epithelioid mesothelioma
Other Exclusions
Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site).
Judgment by the investigator that the participant should not participate in the study if the participant is unlikely to comply with study procedures, restrictions, and requirements.
Participants must refrain from breastfeeding and must not donate, or retrieve for their own use, ova from enrolment throughout the study and until 90 days after last dose of volrustomig, and 180 days or per local prescribing information after the last dose of all other study treatments.
Participants must refrain from fathering a child or donating sperm from enrolment, throughout the study and until 90 days after the last dose of volrustomig, and 180 days or per local prescribing information after the last dose of all other study treatments.
