Clinical Trials /

Carboplatin/Nab-Paclitaxel and Pembrolizumab in NSCLC

NCT02382406

Description:

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.

Related Conditions:
  • Non-Small Cell Lung Carcinoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Carboplatin/Nab-Paclitaxel and Pembrolizumab in NSCLC
  • Official Title: A Phase I/II Study of Carboplatin/Nab-Paclitaxel and Pembrolizumab for Patients With Advanced Non-Small Cell Lung Cancer (NSCLC)

Clinical Trial IDs

  • ORG STUDY ID: HCRN LUN13-175
  • NCT ID: NCT02382406

Conditions

  • Non-Small Cell Lung Cancer

Interventions

DrugSynonymsArms
CarboplatinParaplatinArm A: Phase I Dose Finding Cohort
Nab-paclitaxelAbraxaneArm A: Phase I Dose Finding Cohort
MK-3475 (Phase I)PembrolizumabArm A: Phase I Dose Finding Cohort
MK-3475 (Phase II)PembrolizumabArm B: Phase II Investigational Treatment

Purpose

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.

Detailed Description

      OUTLINE: This is a multi-center study.

      INVESTIGATIONAL TREATMENT:

      Phase I, Cohort 1 Induction Therapy:

        -  Carboplatin AUC 6 IV, Day 1

        -  Nab-paclitaxel 100 mg/m^2 IV, Days 1, 8, 15

        -  pembrolizumab 2 mg/kg IV, Day 1

        -  Cycle length: 21 days; number of cycles: 4

      Phase I, Cohort 1 Maintenance Therapy:

      For subjects who have confirmed CR, PR, or SD (non-progression) after 4 cycles of induction
      therapy, maintenance therapy with pembrolizumab 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 Cycle 1, Day 1 (C1D1). Subjects who complete 24 months of
      treatment with pembrolizumab may be eligible for up to one year of additional study treatment
      if they progress after stopping study treatment provided they continue to meet inclusion
      criteria requirements.

      If unacceptable toxicity is seen in Phase I, Cohort 1, 12 additional participants will be
      enrolled.

      Phase I, Cohort 2 Induction Therapy (if necessary):

        -  Carboplatin AUC 6 IV, Day 1

        -  Nab-paclitaxel 100 mg/m^2 IV, Days 1, 8, 15

        -  pembrolizumab 2 mg/kg IV, Day 1 (cycle 2-4 only)

        -  Cycle length: 21 days; Number of cycles: 4

      Phase I, Cohort 2 Maintenance Therapy:

      For subjects who have confirmed CR, PR, or SD (non-progression) after 4 cycles of induction
      therapy, maintenance therapy with pembrolizumab 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 Cycle 2, Day 1 (C2D1). Subjects who complete 24 months of
      treatment with pembrolizumab may be eligible for up to one year of additional study treatment
      if they progress after stopping study treatment provided they continue to meet inclusion
      criteria requirements.

      Phase II Induction Therapy:

        -  Carboplatin AUC 6 IV, Day 1

        -  Nab-paclitaxel 100 mg/m^2 IV, Days 1, 8, 15

        -  pembrolizumab 200mg IV, Day 1 of each cycle

        -  Cycle length: 21 days; number of cycles: 4

      Phase II Maintenance Therapy:

      For subjects who have confirmed CR, PR, or SD (non-progression) after 4 cycles of induction
      therapy, maintenance therapy with pembrolizumab 200 mg 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 Cycle 1, Day 1 (C1D1). Subjects who complete 24 months of treatment
      with pembrolizumab may be eligible for up to one year of additional study treatment if they
      progress after stopping study treatment provided they meet the requirements.

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

Trial Arms

NameTypeDescriptionInterventions
Arm A: Phase I Dose Finding CohortExperimentalTwelve 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).
  • Carboplatin
  • Nab-paclitaxel
  • MK-3475 (Phase I)
Arm B: Phase II Investigational TreatmentExperimentalSubjects 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.
  • Carboplatin
  • Nab-paclitaxel
  • MK-3475 (Phase II)

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

Primary Outcome Measures

Measure: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.
Safety Issue:
Description: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.

Secondary Outcome Measures

Measure: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)
Safety Issue:
Description: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.
Measure: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]).
Safety Issue:
Description:To evaluate anti-tumor activity for phase I participants using change in tumor measurements per RECIST 1.1 criteria
Measure:Phase I: Overall Survival (OS)
Time Frame:From date of registration to date of death from any cause
Safety Issue:
Description:To evaluate overall survival rates for phase I participants receiving MK-3475 and carboplatin/nab-paclitaxel for the first line treatment of advanced NSCLC.
Measure: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]).
Safety Issue:
Description: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.
Measure:Phase II: Overall Survival (OS)
Time Frame:From date of registration to date of death from any cause
Safety Issue:
Description:To evaluate overall survival rates for phase II participants receiving MK-3475 and carboplatin/nab-paclitaxel for the first line treatment of advanced NSCLC.
Measure: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]).
Safety Issue:
Description:To evaluate anti-tumor activity for phase II participants using change in tumor measurements per RECIST 1.1 criteria
Measure: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.
Safety Issue:
Description: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
Measure: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]).
Safety Issue:
Description: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.

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Active, not recruiting
Lead Sponsor:Nisha Mohindra, MD

Trial Keywords

  • MK-3475
  • Pembrolizumab
  • Carboplatin
  • Nab-paclitaxel

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