Clinical Trials /

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

NCT03126630

Description:

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.

Related Conditions:
  • Pleural Mesothelioma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Pembrolizumab With or Without Anetumab Ravtansine in Treating Patients With Mesothelin-Positive Pleural Mesothelioma
  • Official Title: Phase 1 Safety Run-in and Phase 2 Randomized Clinical Trial of Anetumab Ravtansine and Pembrolizumab Compared to Pembrolizumab for Mesothelin-Positive Malignant Pleural Mesothelioma

Clinical Trial IDs

  • ORG STUDY ID: NCI-2017-00633
  • SECONDARY ID: NCI-2017-00633
  • SECONDARY ID: MC1721
  • SECONDARY ID: 10107
  • SECONDARY ID: 10107
  • SECONDARY ID: UM1CA186686
  • NCT ID: NCT03126630

Conditions

  • Mesothelin Positive
  • Pleural Malignant Mesothelioma

Interventions

DrugSynonymsArms
Anetumab RavtansineBAY 94-9343Group II (pembrolizumab, anetumab ravtansine)
PembrolizumabKeytruda, Lambrolizumab, MK-3475, SCH 900475Group I (pembrolizumab)

Purpose

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.

Detailed Description

      PRIMARY OBJECTIVES:

      I. 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 OBJECTIVE:

      I. To determine the progression free survival of anetumab ravtansine and pembrolizumab
      compared to pembrolizumab alone.

      II. 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).

      III. To evaluate the pharmacodynamic effects of anetumab ravtansine and pembrolizumab on
      soluble megakaryocyte potentiating factor (MPF).

      IV. 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.

      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
      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.
    

Trial Arms

NameTypeDescriptionInterventions
Group I (pembrolizumab)Active ComparatorPatients receive 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. Upon radiologic documentation of disease progression, patients pay cross over to Group II.
    Group II (pembrolizumab, anetumab ravtansine)ExperimentalPatients 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.

      Eligibility Criteria

              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:
      
                     -  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
      
              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:
      
                     -  Antineoplastic systemic chemotherapy or biological therapy
      
                     -  Immunotherapy not specified in this protocol
      
                     -  Chemotherapy not specified in this protocol
      
                     -  Investigational agents other than MK-3475
      
                     -  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 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
            
      Maximum Eligible Age:N/A
      Minimum Eligible Age:18 Years
      Eligible Gender:All
      Healthy Volunteers:No

      Primary Outcome Measures

      Measure:Dose limiting toxicity assessed by National Cancer Institute-Common Terminology Criteria for Adverse Events version 4.03
      Time Frame:Up to 21 days
      Safety Issue:
      Description: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.

      Secondary Outcome Measures

      Measure:Change in megakaryocyte potentiating factor levels assessed in tumor
      Time Frame:Baseline up to 2 years
      Safety Issue:
      Description: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.
      Measure: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
      Safety Issue:
      Description: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.
      Measure: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
      Safety Issue:
      Description: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).
      Measure:Mononuclear phagocyte system -FcgammaRs and chemokine mediators of mononuclear phagocyte system
      Time Frame:Up to 2 years
      Safety Issue:
      Description: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.
      Measure:Overall survival
      Time Frame:From registration to death due to any cause, assessed up to 2 years
      Safety Issue:
      Description: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.
      Measure:Overall survival of patients who cross-over
      Time Frame:Time of re-registration to death due to any cause, assessed up to 2 years
      Safety Issue:
      Description:The distribution of survival time will be estimated using the method of Kaplan-Meier.
      Measure:Pharmacokinetics of anetumab ravtansine and pembrolizumab
      Time Frame:Days 1 and 3 of courses 1 and 8
      Safety Issue:
      Description:Assessed by blood samples.
      Measure: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
      Safety Issue:
      Description: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.
      Measure: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
      Safety Issue:
      Description:Will be estimated using the method of Kaplan-Meier.

      Details

      Phase:Phase 1/Phase 2
      Primary Purpose:Interventional
      Overall Status:Not yet recruiting
      Lead Sponsor:National Cancer Institute (NCI)

      Last Updated

      April 20, 2017