Carboplatin/Nab-Paclitaxel and Pembrolizumab in NSCLC

NCT02382406 | Terminated Phase 1 Results DMC

• 1 other identifier: HCRN LUN13-175
• Study Type: interventional
• Target: 46
• Locations: 1 country
• Sites: 5

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.

Conditions

Non-Small Cell Lung Cancer

Keywords

MK-3475; Pembrolizumab; Carboplatin; Nab-paclitaxel

Outcome Measures

Primary Outcomes (3)

• Phase I: Number of Participants With Adverse Events as a Measure of Safety and Tolerability of Recommended Phase II Dose

  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 by summarizing the number of adverse events experienced by subjects.

  Begin C1D1 and every 2 chemotherapy cycles (6 weeks) thereafter, for up to 2 years or until unacceptable toxicity.

• Phase II: Disease Assessment for Progression-Free Survival (PFS)

  To evaluate progression-free survival (PFS) for phase II participants receiving MK-3475 and carboplatin/nab-paclitaxel for the first line treatment of advanced NSCLC per RECIST 1.1 criteria. PFS is defined as the duration of time from date of registration to time of progression or death, whichever occurs first. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions

  From date of registration to time of first documented progression or death, whichever occurs first (estimate 9 months)

• Phase II: Objective Response Rate

  To evaluate objective response rate for phase II participants receiving MK-3475 and carboplatin/nab-paclitaxel for the first line treatment of advanced NSCLC per RECIST 1.1 criteria. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.

  From the start of treatment until progression or death up to 24 months

Secondary Outcomes (8)

• Phase I: Disease Assessment for Progression-Free Survival (PFS)

  From date of registration to time of first documented progression or death, whichever occurs first (estimate 9 months)

• Phase I : Objective Response Rate

  From the start of treatment until progression or death up to 11 months.

• Phase I: Disease Assessment for Anti-Tumor Activity

  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]).

• Phase I: Overall Survival (OS)

  From date of registration to date of death from any cause up to 49 months.

• Phase II: Overall Survival (OS)

  From date of registration to date of death from any cause up to 42 months.

Study Arms (2)

Arm A: Phase I Dose Finding Cohort

EXPERIMENTAL

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; Drug: Nab-paclitaxel; Drug: MK-3475 (Phase I)

Arm B: Phase II Investigational Treatment

EXPERIMENTAL

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; Drug: Nab-paclitaxel; Drug: MK-3475 (Phase II)

Interventions

Carboplatin DRUG

Carboplatin AUC 6 IV, D1 for 4 cycles (cycle = 21 days)

Also known as: Paraplatin

Arm A: Phase I Dose Finding Cohort; Arm B: Phase II Investigational Treatment

Nab-paclitaxel DRUG

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

Also known as: Abraxane

Arm A: Phase I Dose Finding Cohort; Arm B: Phase II Investigational Treatment

MK-3475 (Phase I) DRUG

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.

Also known as: Pembrolizumab

Arm A: Phase I Dose Finding Cohort

MK-3475 (Phase II) DRUG

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.

Also known as: Pembrolizumab

Arm B: Phase II Investigational Treatment

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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

Sponsors & Collaborators

• Nisha Mohindra, MD: lead
• Hoosier Cancer Research Network: collaborator
• Merck Sharp & Dohme LLC: collaborator
• Celgene Corporation: collaborator

Study Sites (5)

City of Hope

Duarte, California, 91010, United States

Location

Northwestern University, Robert H. Lurie Comprehensive Cancer Center

Chicago, Illinois, 60611, United States

Location

Indiana University Melvin and Bren Simon Cancer Center

Indianapolis, Indiana, 46202, United States

Location

IU Health Central Indiana Cancer Center

Indianapolis, Indiana, 46219, United States

Location

University of Virginia Cancer Center

Charlottesville, Virginia, 22908, United States

Location

Related Links

• Hoosier Cancer Research Network Website

MeSH Terms

Conditions

Carcinoma, Non-Small-Cell Lung

Interventions

Carboplatin; 130-nm albumin-bound paclitaxel; Albumin-Bound Paclitaxel; pembrolizumab; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic

Condition Hierarchy (Ancestors)

Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Neoplasms; Lung Diseases; Respiratory Tract Diseases

Intervention Hierarchy (Ancestors)

Coordination Complexes; Organic Chemicals; Paclitaxel; Taxoids; Cyclodecanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Hydrocarbons; Diterpenes; Terpenes; Albumins; Proteins; Amino Acids, Peptides, and Proteins; Clinical Trials as Topic; Clinical Studies as Topic; Epidemiologic Study Characteristics; Epidemiologic Methods; Investigative Techniques; Health Care Evaluation Mechanisms; Quality of Health Care; Health Care Quality, Access, and Evaluation; Public Health; Environment and Public Health

Results Point of Contact

• Title: Annesha Majumdar
• Organization: Hoosier Cancer Research Network

amajumdar@hoosiercancer.org

3179212050

Study Officials

• Nisha Mohindra, M.D.

  Hoosier Cancer Research Network

  STUDY CHAIR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Sponsor-Investigator

Study Record Dates

• First Submitted: February 24, 2015
• First Posted: March 6, 2015
• Study Start: June 4, 2015
• Primary Completion: April 14, 2022
• Study Completion: April 14, 2022
• Last Updated: May 23, 2023
• Results First Posted: October 14, 2022

Record last verified: 2022-09

Data Sharing

• IPD Sharing: Will not share

Locations

US (5)