Pembrolizumab With or Without Anetumab Ravtansine in Treating Patients With Mesothelin-Positive Pleural Mesothelioma

Primary Outcome Measures

• Dose limiting toxicity assessed by National Cancer Institute-Common Terminology Criteria for Adverse Events version 4.03 [ Time Frame: Up to 21 days ] An early safety analysis will be performed after the first 6 patients have been accrued to the safety lead-in portion of the study at dose level 1 and observed for one cycle. If 2 or more of the first 6 patients experience a dose limiting toxicities, then the starting dose level will be adjusted and additional cohorts may be evaluated.
• Overall response rate (Phase II) [ Time Frame: Up to 2 years ]
  The proportion of successes will be estimated in each arm by the number of successes divided by the total number of evaluable patients. Exact binomial ninety-five percent confidence intervals for the true success proportion will be calculated in each arm. Comparison of overall response rates between the two treatment groups will be performed using a one-sided chi-square test at significance level 0.10.

Secondary Outcome Measures

• Change in megakaryocyte potentiating factor levels assessed in tumor [ Time Frame: Baseline up to 2 years ] Relative changes in biomarker levels will be compared by best overall response groups using the non-parametric Wilcoxon rank-sum test. Also, the associations between changes in megakaryocyte potentiating factor levels and ordered response categories (i.e. complete response-partial response-stable disease-progressive disease) will be assessed with the Jonckheere-Terpstra test for trend.
• Duration of response defined as evaluable patients who achieved noted to be a partial response or complete response based Response Evaluation Criteria in Solid Tumors version 1.1 criteria [ Time Frame: Up to 2 years ] Will be estimated using the method of Kaplan-Meier. The comparison of duration of response between two treatment arms will be based on the log-rank test.
• Incidence of adverse events assessed by National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 [ Time Frame: Up to 30 days after last dose of study drug ]
  The maximum grade for each type of adverse event will be recorded for each patient, and frequency tables will be reviewed for each arm to determine patterns. Additionally, the relationship of the adverse event(s) to the study treatment will be taken into consideration. The overall adverse event rates for grade 3 or higher hematologic and non-hematologic adverse events at least possibly related to treatment will be compared between the two treatment groups using the Chi-square test (or Fisher’s exact test if the data in the contingency table is sparse).

• Mononuclear phagocyte system -FcgammaRs and chemokine mediators of mononuclear phagocyte system [ Time Frame: Up to 2 years ] The mean equivalent soluble fluorophore and antibody bound to cell (ABC) will be determined for each specimen. Linear regression will be used to explore the linear relationship between the continuous values of these mononuclear phagocyte system-FcgammaRs probes and anetumab ravtansine levels. The concentrations of CCL2 and CCL5 will be determined for each specimen. Linear regression will be used to explore the linear relationship between the continuous values of these chemokines and anetumab ravtansine levels.
• Overall survival [ Time Frame: From registration to death due to any cause, assessed up to 2 years]
  Will be estimated using the method of Kaplan-Meier. The comparison of overall survival between two treatment arms will be based on the log-rank test.

• Overall survival of patients who cross-over [ Time Frame: Time of re-registration to death due to any cause, assessed up to 2 years ] The distribution of survival time will be estimated using the method of Kaplan-Meier.
• Pharmacokinetics of anetumab ravtansine and pembrolizumab [ Time Frame: Days 1 and 3 of courses 1 and 8 ] Assessed by blood samples.
• Progression free survival [ Time Frame: From registration to the earliest date of documentation of disease progression or death due to any cause, assessed up to 2 years ]
  Will be estimated using the method of Kaplan-Meier. The comparison of progression-free survival between two treatment arms will be based on the log-rank test.

• Progression free survival of patient who cross-over [ Time Frame: Time of re-registration to the earliest date of documentation of disease progression after the cross-over or death due to any cause, assessed up to 2 years ]. Will be estimated using the method of Kaplan-Meier.

Other Outcome Measures

• Measurements of Bim in TTR [ Time Frame: Up to 2 years ]. Measurements of Bim in TTR as a predictor of responses to treatment. Is anticipated that a non-parametric test such as the Mann-Whitney test should be used to compare Bim in TTR between subjects that do and do not respond to therapy.
• Measurements of soluble PD-L1 [ Time Frame: Up to 2 years ]. Measurements of soluble PD-L1 as a predictor of responses to treatment. Is anticipated that a non-parametric test such as the Mann-Whitney test should be used to compare soluble PD-L1 between subjects that do and do not respond to therapy.
• PD-L1 expression in archival tissue [ Time Frame: Up to 2 years ], PD-L1 expression in archival tissue as a predictive marker of response to pembrolizumab-based therapy. Will compare whether there is a difference in the number of responders with 50% or greater PD-L1 tumor cell expression and those without with the Chi-square test (or Fisher’s exact test if the data in the contingency table is sparse).

Detailed Description

Primary Objectives

• Evaluate the safety of anetumab ravtansine and pembrolizumab when given in combination. (Phase I) II. Determine if the overall response rate of the combination of anetumab ravtansine and pembrolizumab is superior to pembrolizumab alone. (Phase II)

Secondary Objectives

• To determine the progression free survival of anetumab ravtansine and pembrolizumab compared to pembrolizumab alone.
• To determine the progression free survival and overall response rate of subjects who cross-over from pembrolizumab to the combination of anetumab ravtansine and pembrolizumab after progression by modified Response Evaluation Criteria in Solid Tumors (mRECIST).
• To evaluate the pharmacodynamic effects of anetumab ravtansine and pembrolizumab on soluble megakaryocyte potentiating factor (MPF).
• To evaluate the pharmacokinetics of anetumab ravtansine and pembrolizumab. V. To evaluate mononuclear phagocyte system (MPS) function, FcgammaRs, hormone and chemokine mediators as methods to evaluate factors affecting the pharmacokinetics and pharmacodynamics of these agents.

Teritary Objectives

• To determine whether elevations in Bim in TTR predict responses to treatment and whether its detection is dynamic with treatment.
• To determine whether soluble PD-L1 predicts responses to treatment and whether its detection is dynamic with treatment.
• To evaluate PD-L1 expression in archival tissue as a predictive marker of response to pembrolizumab-based therapy.

OUTLINE: Patients are randomized to 1 of 2 groups. GROUP I: Patients receive pembrolizumab intravenously (IV) over 30 minutes on day 1. Courses repeat every 21 days for up to 2 years in the absence of disease progression or unacceptable toxicity. Upon radiologic documentation of disease progression, patients pay cross over to Group II. GROUP II: Patients receive pembrolizumab IV over 30 minutes and anetumab ravtansine IV over 1 hours on day 1. Courses repeat every 21 days for up to 2 years in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up for 12 months.

Eligibility

Inclusion Criteria

PRE-REGISTRATION

Patients must have histologically or cytologically confirmed malignant pleural mesothelioma that is positive for mesothelin by a companion assay; a positive assay result is required for patient to be eligible for and registered to the study; submit slides or a tissue block from an archived tissue sample or a fresh tissue sample from biopsy if archived tissue is not available to Ventana Roche for the mesothelin expression assay; central review of pathology will not be performed

REGISTRATION

Patients who participate in the phase 1 portion of the trial are not required to have measurable disease; patients who participate in the randomized phase 2 portion of the clinical trial must have measurable disease; for pleural disease, this is defined as at least one lesion that can be accurately measured perpendicular to the chest wall or mediastinum that is >= 10 mm (>= 1 cm); for extra pleural disease, measurable disease is defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as >= 10 mm (>= 1 cm) for non-nodal lesions and >= 15 mm (>= 1.5 cm) for nodal lesions with spiral computed tomography (CT) scan, magnetic resonance imaging (MRI), or calipers by clinical exam as per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1

Patients must have received platinum-based therapy with or without bevacizumab, but may not have received a PD-1, PD-L1 or PD-L2 inhibitor

Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)

Leukocytes >= 3,000/mcL

Absolute neutrophil count >= 1,500/mcL

Platelets >= 100,000/mcL

Total bilirubin within normal institutional limits

Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional upper limit of normal (ULN)

Creatinine within normal institutional limits OR creatinine clearance >= 60 mL/min/1.73 m^2 for patients with creatinine levels above institutional normal

International normalized ratio (INR) or prothrombin time (PT) =< 1.5 x ULN

Partial thromboplastin time (PTT) or activated PTT (aPTT) =< 1.5 x ULN

Patients on a stable dose of anti-coagulation therapy will be allowed to participate if they have no signs of bleeding or clotting and the INR/PT and PTT/aPTT results are compatible with an acceptable risk-benefit ratio as per the investigator’s discretion

Negative serum pregnancy test for females of child bearing potential; females are considered to not be of child bearing potential if they are either:

1. Postmenopausal (defined as at least 12 months with no menses without an alternative medical cause; in women < 45 years of age, a high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a postmenopausal state in women not using hormonal contraception or hormonal replacement therapy; in the absence of 12 months of amenorrhea, a single FSH measurement is insufficient);
2. Have had a hysterectomy and/or bilateral oophorectomy, bilateral salpingectomy or bilateral tubal ligation/occlusion, at least 6 weeks prior to screening;
3. Has a congenital or acquired condition that prevents childbearing

Requirement to use contraception prior to, during and after the completion of the study; women of child-bearing potential and men must agree to use adequate contraception prior to study entry, for the duration of the study and 4 months after completion of anetumab ravtansine or pembrolizumab administration; acceptable methods of contraception are:

1. Intrauterine device (IUD)
2. Vasectomy of a female patient’s male partner
3. Contraceptive rod implanted into the skin
4. Diaphragm with spermicide (cannot be used in conjunction with cervical cap/spermicide)
5. Cervical cap with spermicide (nulliparous women only)
6. Contraceptive sponge (nulliparous women only)
7. Male condom or female condom (cannot be used together)
8. Hormonal contraceptive: oral contraceptive pill (estrogen/progestin pill or progestin-only pill), contraceptive skin patch, vaginal contraceptive ring, or subcutaneous contraceptive injection
9. Abstinence (relative to heterosexual activity) can be used as the sole method of contraception if it is consistently employed as the patient’s preferred and usual lifestyle and if considered acceptable by local regulatory agencies and Institutional Review Boards (IRBs); periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods, etc.) and withdrawal are not acceptable methods of contraception
10. If there is any question that a patient will not reliably comply with the requirements for contraception, that patient should not be entered into the study; should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately

Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria

Patients who have had chemotherapy or radiotherapy (unless for pain control) within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study

Patients who have not recovered from adverse events due to prior anti-cancer therapy (i.e., have residual toxicities > grade 1); Note: Patients with =< grade 2 neuropathy or =< grade 2 alopecia are an exception to this criterion and may qualify for the study; Note: If patients received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy

Patients who are receiving any other investigational agents

Patients with known brain metastases with progressive neurologic dysfunction, requirement of steroids and lack of improvement on head imaging obtained prior to consent to this clinical trial should be excluded; patients with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging using the identical imaging modality for each assessment, either magnetic resonance imaging [MRI] or computed tomography [CT] scan, for at least 4 weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment; patients with carcinomatosis meningitis should also be excluded.

History of allergic reactions attributed to compounds of similar chemical or biologic composition to anetumab ravtansine or pembrolizumab

Patients receiving any medications or substances that are inhibitors or inducers of CYP3A4 are ineligible; these include herbal preparation containing CYP3A4 inducers (e.g., St. John’s wort), grapefruit and grapefruit juice (CYP3A4 inhibitor) within 2 weeks before the start of study treatment; as part of the enrollment/informed consent procedures, the patient will be counseled on the risk of interactions with other agents and what to do if new medications need to be prescribed or if the patient is considering a new over-the-counter medicine or herbal product

Patients are prohibited from receiving the following therapies during the screening and treatment phases of this trial:

1. Antineoplastic systemic chemotherapy or biological therapy
2. Immunotherapy not specified in this protocol
3. Chemotherapy not specified in this protocol
4. Investigational agents other than MK-3475
5. Radiation therapy
6. Live vaccines within 30 days prior to the first dose of trial treatment and while participating in the trial; examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, chicken pox, yellow fever, rabies, Bacillus Chalmette-Guerin (BCG), and typhoid (oral) vaccine; seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (e.g., Flu-Mist) are live attenuated vaccines, and are not allowed
7. Systemic glucocorticoids for any purpose other than to modulate symptoms from an event of suspected immunologic etiology; the use of physiologic doses of corticosteroids may be approved after consultation with the study principal investigator (PI) and CTEP

Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements

Pregnant women are excluded from this study; breastfeeding should be discontinued if the mother is treated with anetumab ravtansine or pembrolizumab

Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible

Patients who are known to have a history of or a finding of corneal epitheliopathy at pre-study are excluded

Known additional malignancy that is progressing or requires active treatment; exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin that has undergone potentially curative therapy, or in situ cervical cancer

Receipt of transfusion of blood products (including platelets or red blood cells) or administration of colony stimulating factors (including granulocyte colony-stimulating factor [G-CSF], granulocyte macrophage colony-stimulating factor [GM-CSF], or recombinant erythropoietin) within 4 weeks prior to study treatment

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