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Carboplatin/Nab-Paclitaxel and Pembrolizumab in NSCLC

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ClinicalTrials.gov Identifier: NCT02382406
Recruitment Status : Active, not recruiting
First Posted : March 6, 2015
Last Update Posted : February 11, 2020
Sponsor:
Collaborators:
Hoosier Cancer Research Network
Merck Sharp & Dohme Corp.
Celgene Corporation
Information provided by (Responsible Party):
Nisha Mohindra, MD, Hoosier Cancer Research Network

Brief Summary:

This is a phase I/II study for previously untreated subjects with advanced NSCLC. The study will take place in two phases. First, a cohort of twelve participants will be enrolled in phase I part and will be treated with carboplatin, nab-paclitaxel and pembrolizumab. A cohort of twelve subjects will be evaluated for safety and tolerability after 2 cycles of therapy. All subjects who receive either nab-paclitaxel or pembrolizumab will be evaluable. If 33% of subjects or less have unacceptable toxicity in the first cohort or any subsequent cohort (if necessary), the study will proceed to the Phase II part. If more than 33% have unacceptable toxicity, 12 additional subjects will be enrolled in a second cohort, if necessary. If unacceptable toxicity is seen in more than 33% in Cohort 2, the study will end due to unacceptable toxicity of this drug combination.

The phase II part of the study is a single arm study. All subjects will be treated with carboplatin, nab-paclitaxel, and pembrolizumab in 21-day cycles for up to 4 cycles.

Mandatory pre-treatment tumor biopsies will be obtained prior to initiating treatment for all subjects (only if adequate archived samples are unavailable). Mandatory tumor biopsies will be obtained in the Phase II part of the study after 4 cycles of study treatment or at the time of progression, whichever comes first.

For subjects without progression of disease after Cycle 4, pembrolizumab will continue every 3 weeks for up to 2 years or until unacceptable toxicity.


Condition or disease Intervention/treatment Phase
Non-Small Cell Lung Cancer Drug: Carboplatin Drug: Nab-paclitaxel Drug: MK-3475 (Phase I) Drug: MK-3475 (Phase II) Phase 1 Phase 2

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 46 participants
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase I/II Study of Carboplatin/Nab-Paclitaxel and Pembrolizumab for Patients With Advanced Non-Small Cell Lung Cancer (NSCLC)
Study Start Date : June 2015
Estimated Primary Completion Date : December 2020
Estimated Study Completion Date : December 2021

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Arm A: Phase I Dose Finding Cohort

Twelve subjects will be enrolled and treated with carboplatin AUC 6 IV on Day 1, nab-paclitaxel 100 mg/m^2 IV on Day 1, Day 8, and Day 15, pembrolizumab 2* mg/kg IV on Day 1 for 4 cycles. pembrolizumab (Phase I) treatment for Cohort 1 will continue for a maximum duration of 4 21-day cycles

Phase I, Cohort 1 Maintenance Therapy:

Participants who have confirmed CR, PR, or SD (non-progression) after 4 cycles, maintenance therapy with MK-3475 2* mg/kg will continue on D1 of each 21-day cycle. Treatment will continue until progression of disease, unacceptable toxicity, or a maximum of 2 years from C1D1.

If unacceptable toxicity is seen in Phase I Cohort 1, 12 additional participants will be enrolled in Cohort 2 and treated with carboplatin AUC 6 IV on D1, nab-paclitaxel 100 mg/m2 IV on D1, D8, and D15, MK-3475 2*mg/kg IV on D1 starting C2. MK-3475 (Phase 1) treatment for Cohort 2 will continue for a maximum duration of 3 21-day cycles (C2-4 only).

Drug: Carboplatin
Carboplatin AUC 6 IV, D1 for 4 cycles (cycle = 21 days)
Other Name: Paraplatin

Drug: Nab-paclitaxel
Nab-paclitaxel 100 mg/m2 IV, D1, D8, D15 for 4 cycles (cycle = 21 days)
Other Name: Abraxane

Drug: MK-3475 (Phase I)

MK-3475 2 mg/kg IV, D1 for 4 cycles (Cohort 1) or 3 cycles (Cohort 2) (cycle = 21 days)

Maintenance MK-3475 2 mg/kg IV continues every 21 days after Cycle 4 for up to 2 years.

Other Name: Pembrolizumab

Experimental: Arm B: Phase II Investigational Treatment

Subjects will be treated with carboplatin AUC 6 given IV on Day 1, nab-paclitaxel 100 mg/m^2 given IV on Day 1, Day 8, and Day 15, and pembrolizumab 200mg IV on Day 1 of each cycle. Pembrolizumab Phase II treatment will continue for a maximum duration of 4 cycles (cycle = 21 days).

Maintenance Therapy For participants who have confirmed CR, PR, or SD (non-progression) after 4 cycles of induction therapy, maintenance therapy with MK-3475 2* mg/kg will continue on Day 1 of each 21-day cycle. Treatment will continue until progression of disease, unacceptable toxicity, or for a maximum of 2 years from C1D1.

*As additional data from ongoing trials becomes available, the dose of MK-3475 may be adjusted.

Drug: Carboplatin
Carboplatin AUC 6 IV, D1 for 4 cycles (cycle = 21 days)
Other Name: Paraplatin

Drug: Nab-paclitaxel
Nab-paclitaxel 100 mg/m2 IV, D1, D8, D15 for 4 cycles (cycle = 21 days)
Other Name: Abraxane

Drug: MK-3475 (Phase II)

MK-3475 200 mg IV Day 1 of each cycle (cycle = 21 days)

Maintenance MK-3475 2 mg/kg IV continues every 21 days after Cycle 4 for up to 2 years.

Other Name: Pembrolizumab




Primary Outcome Measures :
  1. Phase I: Number of Participants with Adverse Events as a Measure of Safety and Tolerability of Recommended Phase II Dose [ Time Frame: Begin C1D1 and every 2 chemotherapy cycles (6 weeks) thereafter, for up to 2 years or until unacceptable toxicity. ]
    To determine the recommended Phase II dose (RP2D) of MK-3475 and evaluate the safety and tolerability of the combination of MK-3475 with carboplatin/nab-paclitaxel for the first line treatment of phase I participants with advanced NSCLC per CTCAE v4.0 criteria.

  2. Phase II: Disease Assessment for Progression-Free Survival (PFS) and Objective Response Rate [ Time Frame: From date of registration to time of first documented progression or death, whichever occurs first (estimate 9 months) ]
    To evaluate progression-free survival (PFS) and objective response for phase II participants receiving MK-3475 and carboplatin/nab-paclitaxel for the first line treatment of advanced NSCLC per RECIST 1.1 criteria.


Secondary Outcome Measures :
  1. Phase I: Disease Assessment for Progression-Free Survival (PFS) and Objective Response Rate [ Time Frame: From date of registration to time of first documented progression or death, whichever occurs first (estimate 9 months) ]
    To evaluate progression-free survival (PFS) and objective response for phase I participants receiving MK-3475 and carboplatin/nab-paclitaxel for the first line treatment of advanced NSCLC per RECIST 1.1 criteria.

  2. Phase I: Disease Assessment for Anti-Tumor Activity [ Time Frame: From date of registration to time of first documented progression. (Measurable disease will be assessed after every 2 chemotherapy cycles [every 6 weeks thereafter for up to 2 years or until unacceptable toxicity]). ]
    To evaluate anti-tumor activity for phase I participants using change in tumor measurements per RECIST 1.1 criteria

  3. Phase I: Overall Survival (OS) [ Time Frame: From date of registration to date of death from any cause ]
    To evaluate overall survival rates for phase I participants receiving MK-3475 and carboplatin/nab-paclitaxel for the first line treatment of advanced NSCLC.

  4. Phase I: Assessment of Association of PD-L1 Expression on PFS [ Time Frame: From date of registration to time of first documented progression. (Measurable disease will be assessed after every 2 chemotherapy cycles [every 6 weeks thereafter for up to 2 years or until unacceptable toxicity]). ]
    To evaluate the association of PD-L1 expression on PFS for phase I participants receiving MK-3475. PD-L1 will be categorized as positive (≥50% expression) or negative (<50% expression) from pre-treatment and post-treatment biopsies. PFS will be summarized by PD-L1 expression.

  5. Phase II: Overall Survival (OS) [ Time Frame: From date of registration to date of death from any cause ]
    To evaluate overall survival rates for phase II participants receiving MK-3475 and carboplatin/nab-paclitaxel for the first line treatment of advanced NSCLC.

  6. Phase II: Disease Assessment for Anti-Tumor Activity [ Time Frame: From date of registration to time of first documented progression. (Measurable disease will be assessed after every 2 chemotherapy cycles [every 6 weeks thereafter for up to 2 years or until unacceptable toxicity]). ]
    To evaluate anti-tumor activity for phase II participants using change in tumor measurements per RECIST 1.1 criteria

  7. Phase II: Number of Participants with Adverse Events as a Measure of Safety and Tolerability [ Time Frame: Begin C1D1 and every 2 cycles (6 weeks) thereafter, for up to 2 years or until unacceptable toxicity. ]
    To evaluate the safety and tolerability of the combination of MK-3475 with carboplatin/nab-paclitaxel for the first line treatment of phase II participants with advanced NSCLC per CTCAE v4.0

  8. Phase II: Assessment of Association of PD-L1 Expression on PFS [ Time Frame: From date of registration to time of first documented progression. (Measurable disease will be assessed after every 2 chemotherapy cycles [every 6 weeks thereafter for up to 2 years or until unacceptable toxicity]). ]
    To evaluate the association of PD-L1 expression on PFS for phase II participants receiving MK-3475. PDl-1 will be categorized as positive (≥50% expression) or negative (<50% expression) from pre-treatment and post-treatment biopsies. PFS will be summarized by PD-L1 expression.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Subjects must be willing and able to provide written informed consent for the trial and HIPAA authorization for release of personal health information. NOTE: HIPAA authorization may be included in the informed consent or obtained separately.
  • Subjects must be ≥ 18 years of age.
  • Individuals with stage IIIB or IV, unresectable non-small cell lung cancer (NSCLC) who have not received prior chemotherapy for Stage IIIB or IV disease, and who are not candidates for curative surgery or radiation therapy.
  • ECOG performance status (PS) 0-1
  • Measurable disease by RECIST v1.1 criteria
  • Prior to registration, all subjects must have archival tissue available. For subjects who have no archival tissue, but have PD-L1 testing results using the Dako 22C3 antibody, subjects will be permitted to enroll without submitting tissue. If the patient has not had prior testing and no acceptable archival tissue is available, subjects must be willing to consent to providing a pre-treatment biopsy for PD-L1 testing. Regardless of PD-L1 testing status, archival tissue will be requested for research testing if available.
  • Phase II subjects must be willing to consent to providing a mandatory post-treatment core biopsy for research if clinical feasible.
  • Women are eligible to participate if they are of non-childbearing potential or have documentation of a negative pregnancy test (serum or urine β-hCG) within 3 days of registration. Sexually active pre-menopausal women of childbearing potential must agree to use adequate, highly effective contraceptive measures, starting with the first dose of study drug and for 120 days after the last dose of last study drug. Effective birth control includes (a) intrauterine device (IUD) plus one barrier method; (b) oral, implantable, or injectable contraceptives plus one barrier method; or (c) 2 barrier methods. Effective barrier methods are male or female condoms, diaphragms, and spermicides (creams or gels that contain a chemical to kill sperm). Women of childbearing potential are those who have not been surgically sterilized or have not been free from menses for ≥ 1 year.
  • Male participants should agree to use an adequate method of contraception starting with the first dose of study drug through 120 days after the last dose of last study drug.

Exclusion Criteria:

  • Individuals with the presence of symptomatic CNS metastases requiring radiation treatment, surgery, or ongoing use of corticosteroids.
  • Untreated or brain metastasis causing any symptoms, such as neurologic deficits or headache. Individuals with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of study drug and any neurologic symptoms have returned to baseline and whole brain radiation or stereotactic radiosurgery completed over 4 weeks prior to registration), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to study treatment.
  • History of solid organ or stem cell transplant requiring immunosuppressive medications.
  • Any prior adjuvant cytotoxic chemotherapy within 12 months of registration. Subjects who received chemotherapy for earlier stage disease more than 12 months prior to study registration are eligible for this trial.
  • Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody (including ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways).
  • Any radiotherapy within 2 weeks prior to registration (4 weeks for brain radiotherapy as noted above).
  • Is currently participating in or has participated in a study of an investigational agent or using an investigational device within 4 weeks of the first dose of treatment.
  • History of other invasive malignancy that is currently active and/or has been treated within 12 months of registration. (Notable exceptions include: basal cell carcinoma, squamous cell carcinoma of the skin, localized prostate cancer, in situ carcinomas of the cervix and breast, and superficial bladder cancers [non-muscle-invasive]).
  • Has known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
  • Active autoimmune disease that has required systemic treatment in past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
  • Pulmonary conditions such as sarcoidosis, silicosis, idiopathic pulmonary fibrosis, or hypersensitivity pneumonitis.
  • Has a history of pneumonitis that required steroids or current pneumonitis.
  • Pre-existing peripheral neuropathy that is ≥ Grade 2 by CTCAE v 4.0 criteria.
  • Known significant liver disease including viral, alcoholic, active hepatitis B or C, and/or cirrhosis.
  • Abnormal liver or renal function as defined as: bilirubin ≥ 1.5 mg/dL; AST or ALT ≥ 2.5 x the ULN; alkaline phosphatase > 2.5 x the ULN, there is no upper limit if bone metastasis is present in the absence of liver metastasis; creatinine > 1.5 mg/dL
  • Abnormal baseline hematologic or coagulation parameters as defined as: absolute neutrophil count (ANC) <1.5 x 10^9/L; hemoglobin < 9.0 g/dL; platelets < 100 x 10^9/L; International Normalized Ratio (INR) of prothrombin time (PT) ≥ 1.5 x ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants; Activated Partial Thromboplastin Time (aPTT) ≥ 1.5 x ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants
  • Has received a live vaccine within 30 days prior to the first dose of study drug.
  • Known activating EGFR mutation or ALK translocation
  • Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of pembrolizumab.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02382406


Locations
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United States, California
City of Hope
Duarte, California, United States, 91010
United States, Illinois
Northwestern University, Robert H. Lurie Comprehensive Cancer Center
Chicago, Illinois, United States, 60611
United States, Indiana
Indiana University Melvin and Bren Simon Cancer Center
Indianapolis, Indiana, United States, 46202
IU Health Central Indiana Cancer Center
Indianapolis, Indiana, United States, 46219
United States, Virginia
University of Virginia Cancer Center
Charlottesville, Virginia, United States, 22908
Sponsors and Collaborators
Nisha Mohindra, MD
Hoosier Cancer Research Network
Merck Sharp & Dohme Corp.
Celgene Corporation
Investigators
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Study Chair: Nisha Mohindra, M.D. Hoosier Cancer Research Network
Additional Information:
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Responsible Party: Nisha Mohindra, MD, Sponsor-Investigator, Hoosier Cancer Research Network
ClinicalTrials.gov Identifier: NCT02382406    
Other Study ID Numbers: HCRN LUN13-175
First Posted: March 6, 2015    Key Record Dates
Last Update Posted: February 11, 2020
Last Verified: February 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Keywords provided by Nisha Mohindra, MD, Hoosier Cancer Research Network:
MK-3475
Pembrolizumab
Carboplatin
Nab-paclitaxel
Additional relevant MeSH terms:
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Lung Neoplasms
Carcinoma, Non-Small-Cell Lung
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Neoplasms
Lung Diseases
Respiratory Tract Diseases
Carcinoma, Bronchogenic
Bronchial Neoplasms
Paclitaxel
Carboplatin
Pembrolizumab
Antineoplastic Agents, Phytogenic
Antineoplastic Agents
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents, Immunological