PRIMARY OBJECTIVES:
I. Determine the dose of anetumab ravtansine that is safe in combination with 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 pembrolizumab is superior
to pembrolizumab alone. (Phase II)
SECONDARY OBJECTIVES:
I. To determine the progression free survival of anetumab ravtansine and pembrolizumab
compared to MK-3475 (pembrolizumab) alone.
II. To evaluate the pharmacodynamic effects of anetumab ravtansine and pembrolizumab on
soluble megakaryocyte potentiating factor (MPF).
III. To evaluate the pharmacokinetics of anetumab ravtansine and 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.
CORRELATIVE STUDY OBJECTIVES:
I. To determine whether elevations in Bim in tumor-reactive T cells (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
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. Cycles
repeat every 21 days for up to 24 months 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. Cycles repeat every 21 days for up to 12 months for anetumab ravtansine and
up to 24 months for pembrolizumab 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
- Patient is willing to submit a tissue sample to test for expression of mesothelin
- Note: Tissue sample for mesothelin assay may have been collected 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
- Patients must have received platinum based chemotherapy
- REGISTRATION
- For phase 2 only:
- Patient has measurable disease per Response Evaluation Criteria in Solid Tumors
(RECIST) 1.1 for non-pleural disease or modified RECIST 1.1 (mRECIST) for pleural
disease
- Note: 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 RECIST 1.1
- Tissue submitted for testing at pre-registration shows moderate or stronger mesothelin
expression in >= 30% of the tumor cells
- For phase 1 and 2:
- Patients must have received platinum-based therapy with or without bevacizumab
- Eastern Cooperative Oncology Group (ECOG) performance status < 2 (Karnofsky >= 70%)
- 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 AND partial
thromboplastin time (PTT) or activated PTT (aPTT) =< 1.5 x ULN, unless patient is on
stable dose of anti-coagulation therapy in which case patients 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
- Note: Females are considered to not be of child bearing potential if any of the
following apply:
- 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
- Patient agrees to use one of the following acceptable methods of contraception prior
to study entry, during study participation, and for at least six months after
receiving the last dose of study treatment:
- Acceptable methods of contraception are:
- Single method (1 of the following is acceptable):
- Abstinence, if consistently employed as the patient's preferred and
usual lifestyle and if considered acceptable by local regulatory
agencies and Institutional Review Boards (IRBs)
- 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
- Ability to understand and the willingness to sign a written informed consent document,
unless patient is of impaired decision making capacity in which case patient 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 because of their poor prognosis and
because they would confound the evaluation of neurologic and other adverse events
- Note: 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
- Note: 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 strong inhibitors or
inducers of CYP3A4, including 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
- Patients are prohibited from receiving the following therapies during the screening
and treatment phases (including retreatment for post-complete response relapse) 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 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
- Women who are pregnant or breastfeeding.
- Note: Pregnant women are excluded from this study because anetumab ravtansine and
pembrolizumab are agents with the potential for teratogenic or abortifacient
effects; because there is an unknown but potential risk for adverse events in
nursing infants secondary to treatment of the mother with anetumab ravtansine and
pembrolizumab, breastfeeding should be discontinued if the mother is treated with
anetumab ravtansine or pembrolizumab
- Human immunodeficiency virus (HIV)-positive patients who do not meet all of the
following and/or are on HIV medications considered to be strong inhibitors or inducers
of CYP3A4:
- Undetectable HIV viral load by standard clinical assay within 6 months of
registration
- Willing to adhere to antiretroviral therapy that has minimal overlapping toxicity
or pharmacokinetic interactions with protocol therapy
- 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
- Has a known history of hepatitis B (defined as hepatitis B surface antigen [HBsAg]
reactive) or known active hepatitis C virus (defined as HCV ribonucleic acid [RNA]
[qualitative] is detected) infection
- Note: No testing for hepatitis B and hepatitis C is required unless mandated by
local health authority
- Patients who are known to have a history of or a finding of corneal epitheliopathy at
pre-study are excluded because anetumab ravtansine may worsen this condition and
reduce vision
- 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
- Patient has received prior treatment with PD-1, PD-L1 or PD-L2 inhibitor
