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

Primary Purpose

Pleural Malignant Mesothelioma

Status
Active
Phase
Phase 1
Locations
International
Study Type
Interventional
Intervention
Anetumab Ravtansine
Laboratory Biomarker Analysis
Pembrolizumab
Pharmacological Study
Sponsored by
National Cancer Institute (NCI)
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Pleural Malignant Mesothelioma

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • University of Alabama at Birmingham Cancer Center
  • Mayo Clinic Hospital in Arizona
  • Mayo Clinic in Arizona
  • City of Hope Comprehensive Cancer Center
  • UC San Diego Moores Cancer Center
  • Los Angeles County-USC Medical Center
  • USC / Norris Comprehensive Cancer Center
  • USC Norris Oncology/Hematology-Newport Beach
  • UCHealth University of Colorado Hospital
  • UM Sylvester Comprehensive Cancer Center at Aventura
  • UM Sylvester Comprehensive Cancer Center at Coral Gables
  • UM Sylvester Comprehensive Cancer Center at Deerfield Beach
  • Mayo Clinic in Florida
  • University of Miami Miller School of Medicine-Sylvester Cancer Center
  • UM Sylvester Comprehensive Cancer Center at Kendall
  • UM Sylvester Comprehensive Cancer Center at Plantation
  • Northwestern University
  • University of Chicago Comprehensive Cancer Center
  • University of Kentucky/Markey Cancer Center
  • University of Maryland/Greenebaum Cancer Center
  • Johns Hopkins University/Sidney Kimmel Cancer Center
  • Massachusetts General Hospital Cancer Center
  • Dana-Farber Cancer Institute
  • Mayo Clinic in Rochester
  • Siteman Cancer Center at West County Hospital
  • Washington University School of Medicine
  • Siteman Cancer Center-South County
  • Siteman Cancer Center at Saint Peters Hospital
  • Duke University Medical Center
  • University of Pittsburgh Cancer Institute (UPCI)
  • UT Southwestern/Simmons Cancer Center-Dallas
  • Huntsman Cancer Institute/University of Utah
  • University Health Network-Princess Margaret Hospital

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Experimental

Arm Label

Group I (pembrolizumab)

Group II (anetumab ravtansine, pembrolizumab)

Arm Description

Patients receive pembrolizumab 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.

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.

Outcomes

Primary Outcome Measures

Recommended phase 2 dose of anetumab ravtansine with combination of pembrolizumab
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.
Confirmed tumor response rate (Phase II)
Will be assessed using Response Evaluation Criteria in Solid Tumors version 1.1 criteria. The proportion of successes will be estimated in each group by the number of successes divided by the total number of evaluable patients. Confidence intervals for the true success proportion will be calculated in each arm. Comparison of confirmed response rates between the two treatment groups will be performed using a one-sided z-test with pooled variance at significance level 0.10.

Secondary Outcome Measures

Duration of response
Will be 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. 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.
Overall survival
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.
Progression free survival
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.
Incidence of adverse events
Will be assessed by National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. 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).
Pharmacokinetics of anetumab ravtansine
Will be largely descriptive. Changes over time will be plotted and assessed for each patient.
Change in megakaryocyte potentiating factor levels assessed in tumor
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.
Mononuclear phagocyte system -FcgammaRs and chemokine mediators of mononuclear phagocyte system
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.

Full Information

First Posted
April 20, 2017
Last Updated
September 23, 2023
Sponsor
National Cancer Institute (NCI)
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1. Study Identification

Unique Protocol Identification Number
NCT03126630
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 (MK-3475) Compared to Pembrolizumab Alone for Mesothelin-Positive Malignant Pleural Mesothelioma
Study Type
Interventional

2. Study Status

Record Verification Date
September 2023
Overall Recruitment Status
Active, not recruiting
Study Start Date
October 4, 2018 (Actual)
Primary Completion Date
July 8, 2023 (Actual)
Study Completion Date
September 21, 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
National Cancer Institute (NCI)

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

Brief Summary
This phase I/II trial studies the side effects and how well pembrolizumab with or without anetumab ravtansine works in treating patients with mesothelin-positive pleural mesothelioma. Anetumab ravtansine is a monoclonal antibody, called anetumab, linked to a chemotherapy drug, called ravtansine. Anetumab is a form of targeted therapy because it attaches to specific molecules (receptors) on the surface of cancer cells, known as mesothelin receptors, and delivers ravtansine to kill them. Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving pembrolizumab and anetumab ravtansine may work better in treating patients with mesothelin-positive pleural mesothelioma.
Detailed Description
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 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Pleural Malignant Mesothelioma

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Crossover Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
46 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Group I (pembrolizumab)
Arm Type
Active Comparator
Arm Description
Patients receive pembrolizumab 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.
Arm Title
Group II (anetumab ravtansine, pembrolizumab)
Arm Type
Experimental
Arm Description
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.
Intervention Type
Biological
Intervention Name(s)
Anetumab Ravtansine
Other Intervention Name(s)
BAY 94-9343
Intervention Description
Given IV
Intervention Type
Other
Intervention Name(s)
Laboratory Biomarker Analysis
Intervention Description
Correlative studies
Intervention Type
Biological
Intervention Name(s)
Pembrolizumab
Other Intervention Name(s)
BCD-201, Keytruda, Lambrolizumab, MK-3475, Pembrolizumab Biosimilar BCD-201, SCH 900475
Intervention Description
Given IV
Intervention Type
Other
Intervention Name(s)
Pharmacological Study
Intervention Description
Correlative studies
Primary Outcome Measure Information:
Title
Recommended phase 2 dose of anetumab ravtansine with combination of pembrolizumab
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.
Time Frame
Up to 21 days
Title
Confirmed tumor response rate (Phase II)
Description
Will be assessed using Response Evaluation Criteria in Solid Tumors version 1.1 criteria. The proportion of successes will be estimated in each group by the number of successes divided by the total number of evaluable patients. Confidence intervals for the true success proportion will be calculated in each arm. Comparison of confirmed response rates between the two treatment groups will be performed using a one-sided z-test with pooled variance at significance level 0.10.
Time Frame
Up to 2 years
Secondary Outcome Measure Information:
Title
Duration of response
Description
Will be 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. 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.
Time Frame
Up to 2 years
Title
Overall survival
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.
Time Frame
From the start of treatment to death due to any cause, assessed up to 2 years
Title
Progression free survival
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.
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
Title
Incidence of adverse events
Description
Will be assessed by National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. 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).
Time Frame
Up to 30 days after last dose of study drug
Title
Pharmacokinetics of anetumab ravtansine
Description
Will be largely descriptive. Changes over time will be plotted and assessed for each patient.
Time Frame
Days 1 and 3 of courses 1 and 8
Title
Change in megakaryocyte potentiating factor levels assessed in tumor
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.
Time Frame
Baseline up to 2 years
Title
Mononuclear phagocyte system -FcgammaRs and chemokine mediators of mononuclear phagocyte system
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.
Time Frame
Up to 2 years
Other Pre-specified Outcome Measures:
Title
Measurements of Bim in tumor-reactive T cells (TTR)
Description
Measurements of Bim in TTR as a predictor of responses to treatment. Is anticipated that a non-parametric test such as the Mann-Whitney test should be used to compare Bim in TTR between subjects that do and do not respond to therapy.
Time Frame
Up to 2 years
Title
Measurements of soluble PD-L1
Description
Measurements of soluble PD-L1 as a predictor of responses to treatment. Is anticipated that a non-parametric test such as the Mann-Whitney test should be used to compare soluble PD-L1 between subjects that do and do not respond to therapy.
Time Frame
Up to 2 years
Title
PD-L1 expression in archival tissue
Description
PD-L1 expression in archival tissue as a predictive marker of response to pembrolizumab-based therapy. Will compare whether there is a difference in the number of responders with 50% or greater PD-L1 tumor cell expression and those without with the Chi-square test (or Fisher's exact test if the data in the contingency table is sparse).
Time Frame
Up to 2 years
Title
Patient reported outcomes-Common Terminology Criteria for Adverse Events
Time Frame
Up to 2 years

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Aaron S Mansfield
Organizational Affiliation
Dana-Farber - Harvard Cancer Center LAO
Official's Role
Principal Investigator
Facility Information:
Facility Name
University of Alabama at Birmingham Cancer Center
City
Birmingham
State/Province
Alabama
ZIP/Postal Code
35233
Country
United States
Facility Name
Mayo Clinic Hospital in Arizona
City
Phoenix
State/Province
Arizona
ZIP/Postal Code
85054
Country
United States
Facility Name
Mayo Clinic in Arizona
City
Scottsdale
State/Province
Arizona
ZIP/Postal Code
85259
Country
United States
Facility Name
City of Hope Comprehensive Cancer Center
City
Duarte
State/Province
California
ZIP/Postal Code
91010
Country
United States
Facility Name
UC San Diego Moores Cancer Center
City
La Jolla
State/Province
California
ZIP/Postal Code
92093
Country
United States
Facility Name
Los Angeles County-USC Medical Center
City
Los Angeles
State/Province
California
ZIP/Postal Code
90033
Country
United States
Facility Name
USC / Norris Comprehensive Cancer Center
City
Los Angeles
State/Province
California
ZIP/Postal Code
90033
Country
United States
Facility Name
USC Norris Oncology/Hematology-Newport Beach
City
Newport Beach
State/Province
California
ZIP/Postal Code
92663
Country
United States
Facility Name
UCHealth University of Colorado Hospital
City
Aurora
State/Province
Colorado
ZIP/Postal Code
80045
Country
United States
Facility Name
UM Sylvester Comprehensive Cancer Center at Aventura
City
Aventura
State/Province
Florida
ZIP/Postal Code
33180
Country
United States
Facility Name
UM Sylvester Comprehensive Cancer Center at Coral Gables
City
Coral Gables
State/Province
Florida
ZIP/Postal Code
33146
Country
United States
Facility Name
UM Sylvester Comprehensive Cancer Center at Deerfield Beach
City
Deerfield Beach
State/Province
Florida
ZIP/Postal Code
33442
Country
United States
Facility Name
Mayo Clinic in Florida
City
Jacksonville
State/Province
Florida
ZIP/Postal Code
32224-9980
Country
United States
Facility Name
University of Miami Miller School of Medicine-Sylvester Cancer Center
City
Miami
State/Province
Florida
ZIP/Postal Code
33136
Country
United States
Facility Name
UM Sylvester Comprehensive Cancer Center at Kendall
City
Miami
State/Province
Florida
ZIP/Postal Code
33176
Country
United States
Facility Name
UM Sylvester Comprehensive Cancer Center at Plantation
City
Plantation
State/Province
Florida
ZIP/Postal Code
33324
Country
United States
Facility Name
Northwestern University
City
Chicago
State/Province
Illinois
ZIP/Postal Code
60611
Country
United States
Facility Name
University of Chicago Comprehensive Cancer Center
City
Chicago
State/Province
Illinois
ZIP/Postal Code
60637
Country
United States
Facility Name
University of Kentucky/Markey Cancer Center
City
Lexington
State/Province
Kentucky
ZIP/Postal Code
40536
Country
United States
Facility Name
University of Maryland/Greenebaum Cancer Center
City
Baltimore
State/Province
Maryland
ZIP/Postal Code
21201
Country
United States
Facility Name
Johns Hopkins University/Sidney Kimmel Cancer Center
City
Baltimore
State/Province
Maryland
ZIP/Postal Code
21287
Country
United States
Facility Name
Massachusetts General Hospital Cancer Center
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02114
Country
United States
Facility Name
Dana-Farber Cancer Institute
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02215
Country
United States
Facility Name
Mayo Clinic in Rochester
City
Rochester
State/Province
Minnesota
ZIP/Postal Code
55905
Country
United States
Facility Name
Siteman Cancer Center at West County Hospital
City
Creve Coeur
State/Province
Missouri
ZIP/Postal Code
63141
Country
United States
Facility Name
Washington University School of Medicine
City
Saint Louis
State/Province
Missouri
ZIP/Postal Code
63110
Country
United States
Facility Name
Siteman Cancer Center-South County
City
Saint Louis
State/Province
Missouri
ZIP/Postal Code
63129
Country
United States
Facility Name
Siteman Cancer Center at Saint Peters Hospital
City
Saint Peters
State/Province
Missouri
ZIP/Postal Code
63376
Country
United States
Facility Name
Duke University Medical Center
City
Durham
State/Province
North Carolina
ZIP/Postal Code
27710
Country
United States
Facility Name
University of Pittsburgh Cancer Institute (UPCI)
City
Pittsburgh
State/Province
Pennsylvania
ZIP/Postal Code
15232
Country
United States
Facility Name
UT Southwestern/Simmons Cancer Center-Dallas
City
Dallas
State/Province
Texas
ZIP/Postal Code
75390
Country
United States
Facility Name
Huntsman Cancer Institute/University of Utah
City
Salt Lake City
State/Province
Utah
ZIP/Postal Code
84112
Country
United States
Facility Name
University Health Network-Princess Margaret Hospital
City
Toronto
State/Province
Ontario
ZIP/Postal Code
M5G 2M9
Country
Canada

12. IPD Sharing Statement

Learn more about this trial

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

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