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 MK-3475 (Pembrolizumab) Compared to MK-3475 (Pembrolizumab) Alone 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 (anetumab ravtansine, pembrolizumab)
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. 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.
    

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 may cross over to Group II.
  • Pembrolizumab
Group II (anetumab ravtansine, pembrolizumab)ExperimentalPatients 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.
  • Anetumab Ravtansine
  • Pembrolizumab

Eligibility Criteria

        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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Recommended phase 2 dose of anetumab ravtansine with combination of pembrolizumab
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. All patients that have received any amount of the combination anetumab ravtansine and pembrolizumab will be evaluable for toxicity.

Secondary Outcome Measures

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. This calculation will start with the date of start of treatment.
Measure:Overall survival
Time Frame:From the start of treatment 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: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
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: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:Pharmacokinetics of anetumab ravtansine
Time Frame:Days 1 and 3 of courses 1 and 8
Safety Issue:
Description:Will be largely descriptive. Changes over time will be plotted and assessed for each patient.
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: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.

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:National Cancer Institute (NCI)

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