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

PRIMARY OBJECTIVES:

I. Determine the dose of anetumab ravtansine that is safe in combination with MK-3475
(pembrolizumab) to be used in the randomized phase 2 study. (Phase I safety lead-in) II.
Determine if the overall response rate of the combination of anetumab ravtansine and MK-3475
(pembrolizumab) is superior to MK-3475 (pembrolizumab) alone. (Phase II)

SECONDARY OBJECTIVE:

I. To determine the progression free survival of anetumab ravtansine and MK-3475
(pembrolizumab) compared to MK-3475 (pembrolizumab) alone.

II. To evaluate the pharmacodynamic effects of anetumab ravtansine and MK-3475
(pembrolizumab) on soluble megakaryocyte potentiating factor (MPF).

III. To evaluate the pharmacokinetics of anetumab ravtansine and MK-3475 (pembrolizumab).

IV. 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.

V. To determine the incidence of antibodies directed against anetumab ravtansine.

TERTIARY OBJECTIVE:

I. To determine whether elevations in Bim in TTR predict responses to treatment and whether
its detection is dynamic with treatment.

II. To determine whether soluble PD-L1 predicts responses to treatment and whether its
detection is dynamic with treatment.

III. To evaluate PD-L1 expression in archival tissue as a predictive marker of response to
MK-3475 (pembrolizumab)-based therapy.

IV. To explore the symptomatic adverse events (AE) for tolerability of each treatment group
using patient reported outcomes (PRO)-Common Terminology Criteria for Adverse Events (CTCAE).

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 may cross over to
Group II.

GROUP II: Patients receive anetumab ravtansine IV over 1 hour and pembrolizumab 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.

After completion of study treatment, patients are followed up for 12 months.

Inclusion Criteria:

- PRE-REGISTRATION

- Patients must have histologically or cytologically confirmed malignant pleural
mesothelioma; for phase 2 of this study only, the malignant tissue must show moderate
or stronger mesothelin expression in 30% of tumor cells by a companion assay for the
patient to be eligible for and registered to the study; for patients in
pre-registration for phase 2, 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 the
central lab for the mesothelin expression assay; central review of pathology will not
be performed

- Patients must have received platinum based chemotherapy; the submission of a tissue
sample for the mesothelin assay to determine eligibility for the study may occur prior
to, during or after receipt of the frontline chemotherapy; patients will not be
required to submit another tissue sample after receipt of the chemotherapy

- 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:

- 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);

- Have had a hysterectomy and/or bilateral oophorectomy, bilateral salpingectomy or
bilateral tubal ligation/occlusion, at least 6 weeks prior to screening;

- 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:

- Single method (1 of the following is acceptable):

- Intrauterine device (IUD)

- Vasectomy of a female patient's male partner

- Contraceptive rod implanted into the skin

- Combination method (requires use of 2 of the following):

- Diaphragm with spermicide (cannot be used in conjunction with cervical
cap/spermicide)

- Cervical cap with spermicide (nulliparous women only)

- Contraceptive sponge (nulliparous women only)

- Male condom or female condom (cannot be used together)

- Hormonal contraceptive: oral contraceptive pill (estrogen/progestin pill or
progestin-only pill), contraceptive skin patch, vaginal contraceptive ring,
or subcutaneous contraceptive injection

- 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

- 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;
patients with impaired decision making capacity may be eligible if they have a Legal
Authorized representative or caretaker available

Exclusion Criteria:

- Patients who have received any monoclonal antibody therapy within 4 weeks 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 MK-3475 (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:

- Antineoplastic systemic chemotherapy or biological therapy

- Immunotherapy not specified in this protocol

- Chemotherapy not specified in this protocol

- Investigational agents other than anetumab ravtansine and MK-3475 (pembrolizumab)

- Radiation therapy

- Note: Radiation therapy to a symptomatic solitary lesion or to the brain may
be considered on an exceptional case by case basis after consultation with
Cancer Therapy Evaluation Program (CTEP); the patient must have clear
measurable disease outside the radiated field; administration of palliative
radiation therapy will be considered clinical progression for the purposes
of determining progression free survival (PFS)

- 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

- 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 MK-3475 (pembrolizumab)

- Human immunodeficiency virus (HIV)-positive patients are eligible provided they meet
all the other protocol eligibility criteria including the following:

- Undetectable HIV viral load by standard clinical assay

- Willing to adhere to antiretroviral therapy that has minimal overlapping toxicity
or pharmacokinetic interactions with protocol therapy

- CD4+ T cell counts of 200/mm^3 or greater

- No acquired immunodeficiency syndrome (AIDS)-defining events other within the
past 12 months

- Near normal life expectancy if not for the presence of the cancer Also,
HIV-positive patients must not be on HIV medications considered to be inhibitors
or inducers of CYP3A4

- 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

- Patient with active interstitial lung disease (ILD)/pneumonitis or a prior history of
ILD/pneumonitis requiring treatment with steroids