This randomized phase I/II trial studies the side effects and how well pembrolizumab with or without anetumab ravtansine work in treating patients with mesothelin-positive pleural mesothelioma. Monoclonal antibodies, such as anetumab ravtansine and pembrolizumab, may interfere with the ability of tumor cells to grow and spread.
|First Received Date||April 20, 2017|
|Last Changed Date||March 2, 2018|
|Start Date||February 8, 2018|
|Anticipated Primary Completion Date||February 2, 2020|
|Primary Outcome Measures||
Recommended phase 2 dose of anetumab ravtansine with combination of pembrolizumab [Time Frame: Up to 21 days]
Confirmed tumor response rate assessed using Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 criteria (Phase II) [Time Frame: Up to 2 years]
|Secondary Outcome Measures||
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]
Overall survival [Time Frame: From the start of treatment to death due to any cause, assessed up to 2 years]
Progression free survival [Time Frame: From the start of treatment to the earliest date of documentation of disease progression or death due to any cause, assessed up to 2 years]
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]
Pharmacokinetics of anetumab ravtansine [Time Frame: Days 1 and 3 of courses 1 and 8]
Change in megakaryocyte potentiating factor levels assessed in tumor [Time Frame: Baseline up to 2 years]
Mononuclear phagocyte system -FcgammaRs and chemokine mediators of mononuclear phagocyte system [Time Frame: Up to 2 years]
|Phase||Phase 1/Phase 2|
|Study Arms / Comparison Groups||2 / 0|
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)
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.
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 pay 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.
|Ages||18 Years - N/A|
|Accepts Healthy Volunteers||No|
- 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
- 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
- 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
|Sponsor||National Cancer Institute (NCI)|
|Verification Date||February 2018|