Trial Outcomes & Findings for Carboplatin/Nab-Paclitaxel and Pembrolizumab in NSCLC (NCT NCT02382406)

Last Updated: 2023-05-23

Results Overview

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.

Recruitment status

TERMINATED

Study phase

PHASE1/PHASE2

Target enrollment

46 participants

Primary outcome timeframe

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

Results posted on

2023-05-23

Participant Flow

Participant milestones

Participant milestones
Measure	Phase I, Cohort 1 Phase I, Cohort 1: Induction Therapy Twelve subjects will be enrolled to Cohort 1 and treated with carboplatin AUC 6 IV on Day 1, nab-paclitaxel 100 mg/m\^2 given IV on Days 1, 8, and 15, and pembrolizumab 2\* mg/kg IV on Day 1.Treatment will continue for a maximum duration of 4 cycles with cycle length of 21 days. Phase I, Cohort 1 Maintenance Therapy: Participants who have confirmed CR, PR, or SD (non-progression) after 4 cycles, maintenance therapy with pembrolizumab 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.	Phase II Induction Therapy Cycles 1-4 Subjects will be treated with carboplatin AUC 6 given IV on Day 1, nab-paclitaxel 100 mg/m2 given IV on Days 1, 8, and 15, and pembrolizumab 200 mg IV on Day 1. Treatment will continue for a maximum duration of 4 cycles of study treatment. Each cycle starts when all the criteria to start a new cycle are met. A cycle is defined only when you can give all 3 drugs on Day 1, and it coincides with pembrolizumab. Pembrolizumab should be given with carboplatin and nab-paclitaxel on day 1 of the cycle. Chemotherapies may be withheld for six weeks, while pembrolizumab can be withheld for 12-weeks. If there is a pembrolizumab-specific toxicity requiring pembrolizumab to be held, chemotherapy should be resumed without pembrolizumab within 6 weeks if it is felt that chemotherapy is safe by the site investigator. Delays in chemotherapy beyond 6 weeks require withdrawal from the study treatment. 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.
Study Treatment STARTED	14	32
Study Treatment COMPLETED	0	2
Study Treatment NOT COMPLETED	14	30
Follow up STARTED	14	32
Follow up COMPLETED	0	2
Follow up NOT COMPLETED	14	30

Reasons for withdrawal

Reasons for withdrawal
Measure	Phase I, Cohort 1 Phase I, Cohort 1: Induction Therapy Twelve subjects will be enrolled to Cohort 1 and treated with carboplatin AUC 6 IV on Day 1, nab-paclitaxel 100 mg/m\^2 given IV on Days 1, 8, and 15, and pembrolizumab 2\* mg/kg IV on Day 1.Treatment will continue for a maximum duration of 4 cycles with cycle length of 21 days. Phase I, Cohort 1 Maintenance Therapy: Participants who have confirmed CR, PR, or SD (non-progression) after 4 cycles, maintenance therapy with pembrolizumab 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.	Phase II Induction Therapy Cycles 1-4 Subjects will be treated with carboplatin AUC 6 given IV on Day 1, nab-paclitaxel 100 mg/m2 given IV on Days 1, 8, and 15, and pembrolizumab 200 mg IV on Day 1. Treatment will continue for a maximum duration of 4 cycles of study treatment. Each cycle starts when all the criteria to start a new cycle are met. A cycle is defined only when you can give all 3 drugs on Day 1, and it coincides with pembrolizumab. Pembrolizumab should be given with carboplatin and nab-paclitaxel on day 1 of the cycle. Chemotherapies may be withheld for six weeks, while pembrolizumab can be withheld for 12-weeks. If there is a pembrolizumab-specific toxicity requiring pembrolizumab to be held, chemotherapy should be resumed without pembrolizumab within 6 weeks if it is felt that chemotherapy is safe by the site investigator. Delays in chemotherapy beyond 6 weeks require withdrawal from the study treatment. 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.
Study Treatment Disease Progression	8	20
Study Treatment AE/ Side Effects/ Complications	4	6
Study Treatment Patient withdrawal after therapy start	1	1
Study Treatment symptomatic deterioration	1	1
Study Treatment Death	0	2
Follow up Death	11	19
Follow up Symptomatic deterioration	1	1
Follow up Patient Refused Follow-up	1	0
Follow up Study Terminated	1	8
Follow up Withdrawal by Subject	0	2

Baseline Characteristics

Carboplatin/Nab-Paclitaxel and Pembrolizumab in NSCLC

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Phase I, Cohort 1 n=14 Participants Phase I, Cohort 1: Induction Therapy Twelve subjects will be enrolled to Cohort 1 and treated with carboplatin AUC 6 IV on Day 1, nab-paclitaxel 100 mg/m\^2 given IV on Days 1, 8, and 15, and pembrolizumab 2\* mg/kg IV on Day 1.Treatment will continue for a maximum duration of 4 cycles with cycle length of 21 days. Phase I, Cohort 1 Maintenance Therapy: Participants who have confirmed CR, PR, or SD (non-progression) after 4 cycles, maintenance therapy with pembrolizumab 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.	Phase I, Cohort 2 Phase I, Cohort 2: Induction Therapy If unacceptable toxicity is seen in Phase I, Cohort 1, 12 additional subjects will be enrolled in Phase I, Cohort 2. Subjects will be treated with carboplatin AUC 6 given IV on Day 1 and nabpaclitaxel 100 mg/m2 given IV on Days 1, 8, and 15. Pembrolizumab 2\* mg/kg IV will be given on Day 1 starting in cycle 2. Treatment will continue for a maximum duration of 4 cycles (pembrolizumab given Cycles 2 to 4 only). 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.	Phase II n=32 Participants Induction Therapy Cycles 1-4 Subjects will be treated with carboplatin AUC 6 given IV on Day 1, nab-paclitaxel 100 mg/m2 given IV on Days 1, 8, and 15, and pembrolizumab 200 mg IV on Day 1. Treatment will continue for a maximum duration of 4 cycles of study treatment. Each cycle starts when all the criteria to start a new cycle are met. A cycle is defined only when you can give all 3 drugs on Day 1, and it coincides with pembrolizumab. Pembrolizumab should be given with carboplatin and nab-paclitaxel on day 1 of the cycle. Chemotherapies may be withheld for six weeks, while pembrolizumab can be withheld for 12-weeks. If there is a pembrolizumab-specific toxicity requiring pembrolizumab to be held, chemotherapy should be resumed without pembrolizumab within 6 weeks if it is felt that chemotherapy is safe by the site investigator. Delays in chemotherapy beyond 6 weeks require withdrawal from the study treatment. 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.	Total n=46 Participants Total of all reporting groups
Age, Continuous	66 years n=5 Participants	—	65.5 years n=5 Participants	65.5 years n=4 Participants
Sex: Female, Male Female	9 Participants n=5 Participants	—	13 Participants n=5 Participants	22 Participants n=4 Participants
Sex: Female, Male Male	5 Participants n=5 Participants	—	19 Participants n=5 Participants	24 Participants n=4 Participants
Race/Ethnicity, Customized Race · American Indian or Alaska Native	0 Participants n=5 Participants	—	0 Participants n=5 Participants	0 Participants n=4 Participants
Race/Ethnicity, Customized Race · Asian	0 Participants n=5 Participants	—	1 Participants n=5 Participants	1 Participants n=4 Participants
Race/Ethnicity, Customized Race · Black or African American	1 Participants n=5 Participants	—	5 Participants n=5 Participants	6 Participants n=4 Participants
Race/Ethnicity, Customized Race · Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	—	0 Participants n=5 Participants	0 Participants n=4 Participants
Race/Ethnicity, Customized Race · Unknown	4 Participants n=5 Participants	—	0 Participants n=5 Participants	4 Participants n=4 Participants
Race/Ethnicity, Customized Race · White	9 Participants n=5 Participants	—	26 Participants n=5 Participants	35 Participants n=4 Participants
Race/Ethnicity, Customized Ethnicity · Hispanic or Latino	0 Participants n=5 Participants	—	0 Participants n=5 Participants	0 Participants n=4 Participants
Race/Ethnicity, Customized Ethnicity · Non-Hispanic	11 Participants n=5 Participants	—	31 Participants n=5 Participants	42 Participants n=4 Participants
Race/Ethnicity, Customized Ethnicity · Unknown	3 Participants n=5 Participants	—	1 Participants n=5 Participants	4 Participants n=4 Participants
Histology Subtype Adenocarcinoma	10 Participants n=5 Participants	—	11 Participants n=5 Participants	21 Participants n=4 Participants
Histology Subtype Clear Cell (non-component)	0 Participants n=5 Participants	—	0 Participants n=5 Participants	0 Participants n=4 Participants
Histology Subtype Clear Cell Component	0 Participants n=5 Participants	—	0 Participants n=5 Participants	0 Participants n=4 Participants
Histology Subtype Large Cell Carcinoma	0 Participants n=5 Participants	—	0 Participants n=5 Participants	0 Participants n=4 Participants
Histology Subtype Micropapillary Variant	0 Participants n=5 Participants	—	0 Participants n=5 Participants	0 Participants n=4 Participants
Histology Subtype Non-Small Cell Lung Cancer, NOS	0 Participants n=5 Participants	—	1 Participants n=5 Participants	1 Participants n=4 Participants
Histology Subtype Other	0 Participants n=5 Participants	—	0 Participants n=5 Participants	0 Participants n=4 Participants
Histology Subtype Papillary	0 Participants n=5 Participants	—	0 Participants n=5 Participants	0 Participants n=4 Participants
Histology Subtype Poorly Differentiated Carcinoma	0 Participants n=5 Participants	—	3 Participants n=5 Participants	3 Participants n=4 Participants
Histology Subtype Sarcomatoid	0 Participants n=5 Participants	—	0 Participants n=5 Participants	0 Participants n=4 Participants
Histology Subtype Small Cell Carcinoma	0 Participants n=5 Participants	—	0 Participants n=5 Participants	0 Participants n=4 Participants
Histology Subtype Squamous Cell Carcinoma	4 Participants n=5 Participants	—	17 Participants n=5 Participants	21 Participants n=4 Participants
Histology Subtype Transitional Cell Carcinoma	0 Participants n=5 Participants	—	0 Participants n=5 Participants	0 Participants n=4 Participants
Substance use : Number of Cigarettes 1	2 Participants n=5 Participants	—	1 Participants n=5 Participants	3 Participants n=4 Participants
Substance use : Number of Cigarettes 2	2 Participants n=5 Participants	—	6 Participants n=5 Participants	8 Participants n=4 Participants
Substance use : Number of Cigarettes 3	10 Participants n=5 Participants	—	25 Participants n=5 Participants	35 Participants n=4 Participants
Substance use : Number of Cigarettes 9	0 Participants n=5 Participants	—	0 Participants n=5 Participants	0 Participants n=4 Participants
Substance use : Number of Cigars 1	7 Participants n=5 Participants	—	25 Participants n=5 Participants	32 Participants n=4 Participants
Substance use : Number of Cigars 9	7 Participants n=5 Participants	—	7 Participants n=5 Participants	14 Participants n=4 Participants
Substance use : Number of pipefuls 1	7 Participants n=5 Participants	—	26 Participants n=5 Participants	33 Participants n=4 Participants
Substance use : Number of pipefuls 9	7 Participants n=5 Participants	—	6 Participants n=5 Participants	13 Participants n=4 Participants
ECOG 0	6 Participants n=5 Participants	—	8 Participants n=5 Participants	14 Participants n=4 Participants
ECOG 1	8 Participants n=5 Participants	—	23 Participants n=5 Participants	31 Participants n=4 Participants
ECOG Missing	0 Participants n=5 Participants	—	1 Participants n=5 Participants	1 Participants n=4 Participants

PRIMARY outcome

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

Population: No subjects had been enrolled to Phase I, cohort 2.

Outcome measures

Outcome measures
Measure	Phase I, Cohort 1 n=14 Participants Phase I, Cohort 1: Induction Therapy Twelve subjects will be enrolled to Cohort 1 and treated with carboplatin AUC 6 IV on Day 1, nab-paclitaxel 100 mg/m\^2 given IV on Days 1, 8, and 15, and pembrolizumab 2\* mg/kg IV on Day 1.Treatment will continue for a maximum duration of 4 cycles with cycle length of 21 days. Phase I, Cohort 1 Maintenance Therapy: Participants who have confirmed CR, PR, or SD (non-progression) after 4 cycles, maintenance therapy with pembrolizumab 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.	Phase I, Cohort 2 Phase I, Cohort 2: Induction Therapy If unacceptable toxicity is seen in Phase I, Cohort 1, 12 additional subjects will be enrolled in Phase I, Cohort 2. Subjects will be treated with carboplatin AUC 6 given IV on Day 1 and nabpaclitaxel 100 mg/m2 given IV on Days 1, 8, and 15. Pembrolizumab 2\* mg/kg IV will be given on Day 1 starting in cycle 2. Treatment will continue for a maximum duration of 4 cycles (pembrolizumab given Cycles 2 to 4 only).
Phase I: Number of Participants With Adverse Events as a Measure of Safety and Tolerability of Recommended Phase II Dose Patient had at least one adverse event of any grade	14 Participants	0 Participants
Phase I: Number of Participants With Adverse Events as a Measure of Safety and Tolerability of Recommended Phase II Dose Patient had at least one grade 3 or greater adverse event	14 Participants	0 Participants
Phase I: Number of Participants With Adverse Events as a Measure of Safety and Tolerability of Recommended Phase II Dose Patient had at least one grade 3 or greater treatment related adverse event	12 Participants	0 Participants
Phase I: Number of Participants With Adverse Events as a Measure of Safety and Tolerability of Recommended Phase II Dose Patient having serious adverse event	8 Participants	0 Participants

PRIMARY outcome

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

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

Outcome measures

Outcome measures
Measure	Phase I, Cohort 1 n=32 Participants Phase I, Cohort 1: Induction Therapy Twelve subjects will be enrolled to Cohort 1 and treated with carboplatin AUC 6 IV on Day 1, nab-paclitaxel 100 mg/m\^2 given IV on Days 1, 8, and 15, and pembrolizumab 2\* mg/kg IV on Day 1.Treatment will continue for a maximum duration of 4 cycles with cycle length of 21 days. Phase I, Cohort 1 Maintenance Therapy: Participants who have confirmed CR, PR, or SD (non-progression) after 4 cycles, maintenance therapy with pembrolizumab 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.	Phase I, Cohort 2 Phase I, Cohort 2: Induction Therapy If unacceptable toxicity is seen in Phase I, Cohort 1, 12 additional subjects will be enrolled in Phase I, Cohort 2. Subjects will be treated with carboplatin AUC 6 given IV on Day 1 and nabpaclitaxel 100 mg/m2 given IV on Days 1, 8, and 15. Pembrolizumab 2\* mg/kg IV will be given on Day 1 starting in cycle 2. Treatment will continue for a maximum duration of 4 cycles (pembrolizumab given Cycles 2 to 4 only).
Phase II: Disease Assessment for Progression-Free Survival (PFS)	6.2 months Interval 4.6 to 8.5	—

PRIMARY outcome

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

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.

Outcome measures

Outcome measures
Measure	Phase I, Cohort 1 n=32 Participants Phase I, Cohort 1: Induction Therapy Twelve subjects will be enrolled to Cohort 1 and treated with carboplatin AUC 6 IV on Day 1, nab-paclitaxel 100 mg/m\^2 given IV on Days 1, 8, and 15, and pembrolizumab 2\* mg/kg IV on Day 1.Treatment will continue for a maximum duration of 4 cycles with cycle length of 21 days. Phase I, Cohort 1 Maintenance Therapy: Participants who have confirmed CR, PR, or SD (non-progression) after 4 cycles, maintenance therapy with pembrolizumab 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.	Phase I, Cohort 2 Phase I, Cohort 2: Induction Therapy If unacceptable toxicity is seen in Phase I, Cohort 1, 12 additional subjects will be enrolled in Phase I, Cohort 2. Subjects will be treated with carboplatin AUC 6 given IV on Day 1 and nabpaclitaxel 100 mg/m2 given IV on Days 1, 8, and 15. Pembrolizumab 2\* mg/kg IV will be given on Day 1 starting in cycle 2. Treatment will continue for a maximum duration of 4 cycles (pembrolizumab given Cycles 2 to 4 only).
Phase II: Objective Response Rate	16 Participants	—

SECONDARY outcome

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

Population: No subjects had been enrolled to Phase I, Cohort 2.

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. 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

Outcome measures

Outcome measures
Measure	Phase I, Cohort 1 n=14 Participants Phase I, Cohort 1: Induction Therapy Twelve subjects will be enrolled to Cohort 1 and treated with carboplatin AUC 6 IV on Day 1, nab-paclitaxel 100 mg/m\^2 given IV on Days 1, 8, and 15, and pembrolizumab 2\* mg/kg IV on Day 1.Treatment will continue for a maximum duration of 4 cycles with cycle length of 21 days. Phase I, Cohort 1 Maintenance Therapy: Participants who have confirmed CR, PR, or SD (non-progression) after 4 cycles, maintenance therapy with pembrolizumab 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.	Phase I, Cohort 2 Phase I, Cohort 2: Induction Therapy If unacceptable toxicity is seen in Phase I, Cohort 1, 12 additional subjects will be enrolled in Phase I, Cohort 2. Subjects will be treated with carboplatin AUC 6 given IV on Day 1 and nabpaclitaxel 100 mg/m2 given IV on Days 1, 8, and 15. Pembrolizumab 2\* mg/kg IV will be given on Day 1 starting in cycle 2. Treatment will continue for a maximum duration of 4 cycles (pembrolizumab given Cycles 2 to 4 only).
Phase I: Disease Assessment for Progression-Free Survival (PFS)	5.2 months Interval 4.1 to upper limit has not been achieved due to insufficient number of participants with events.	—

SECONDARY outcome

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

Population: No subjects had been enrolled to Phase I, Cohort 2.

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. Objective response rate (ORR), is defined as the proportion of patients with a complete response or partial response to treatment according to Response Evaluation Criteria in Solid Tumors (RECIST).

Outcome measures

Outcome measures
Measure	Phase I, Cohort 1 n=14 Participants Phase I, Cohort 1: Induction Therapy Twelve subjects will be enrolled to Cohort 1 and treated with carboplatin AUC 6 IV on Day 1, nab-paclitaxel 100 mg/m\^2 given IV on Days 1, 8, and 15, and pembrolizumab 2\* mg/kg IV on Day 1.Treatment will continue for a maximum duration of 4 cycles with cycle length of 21 days. Phase I, Cohort 1 Maintenance Therapy: Participants who have confirmed CR, PR, or SD (non-progression) after 4 cycles, maintenance therapy with pembrolizumab 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.	Phase I, Cohort 2 Phase I, Cohort 2: Induction Therapy If unacceptable toxicity is seen in Phase I, Cohort 1, 12 additional subjects will be enrolled in Phase I, Cohort 2. Subjects will be treated with carboplatin AUC 6 given IV on Day 1 and nabpaclitaxel 100 mg/m2 given IV on Days 1, 8, and 15. Pembrolizumab 2\* mg/kg IV will be given on Day 1 starting in cycle 2. Treatment will continue for a maximum duration of 4 cycles (pembrolizumab given Cycles 2 to 4 only).
Phase I : Objective Response Rate	1 Participants	—

SECONDARY outcome

Timeframe: 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]).

Population: No subjects had been enrolled to Phase I, cohort 2.

To evaluate anti-tumor activity for phase I participants will be reported as a percentage change in the sum of the dimensions of all measurable lesions as defined by RECIST 1.1 criteria.

Outcome measures

Outcome measures
Measure	Phase I, Cohort 1 n=14 Participants Phase I, Cohort 1: Induction Therapy Twelve subjects will be enrolled to Cohort 1 and treated with carboplatin AUC 6 IV on Day 1, nab-paclitaxel 100 mg/m\^2 given IV on Days 1, 8, and 15, and pembrolizumab 2\* mg/kg IV on Day 1.Treatment will continue for a maximum duration of 4 cycles with cycle length of 21 days. Phase I, Cohort 1 Maintenance Therapy: Participants who have confirmed CR, PR, or SD (non-progression) after 4 cycles, maintenance therapy with pembrolizumab 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.	Phase I, Cohort 2 Phase I, Cohort 2: Induction Therapy If unacceptable toxicity is seen in Phase I, Cohort 1, 12 additional subjects will be enrolled in Phase I, Cohort 2. Subjects will be treated with carboplatin AUC 6 given IV on Day 1 and nabpaclitaxel 100 mg/m2 given IV on Days 1, 8, and 15. Pembrolizumab 2\* mg/kg IV will be given on Day 1 starting in cycle 2. Treatment will continue for a maximum duration of 4 cycles (pembrolizumab given Cycles 2 to 4 only).
Phase I: Disease Assessment for Anti-Tumor Activity	-6.9457 percent change Interval -11.3 to 0.578	—

SECONDARY outcome

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

Population: No subjects had been enrolled in Phase I. cohort 2

To evaluate overall survival rates for phase I participants receiving MK-3475 and carboplatin/nab-paclitaxel for the first line treatment of advanced NSCLC.

Outcome measures

Outcome measures
Measure	Phase I, Cohort 1 n=14 Participants Phase I, Cohort 1: Induction Therapy Twelve subjects will be enrolled to Cohort 1 and treated with carboplatin AUC 6 IV on Day 1, nab-paclitaxel 100 mg/m\^2 given IV on Days 1, 8, and 15, and pembrolizumab 2\* mg/kg IV on Day 1.Treatment will continue for a maximum duration of 4 cycles with cycle length of 21 days. Phase I, Cohort 1 Maintenance Therapy: Participants who have confirmed CR, PR, or SD (non-progression) after 4 cycles, maintenance therapy with pembrolizumab 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.	Phase I, Cohort 2 Phase I, Cohort 2: Induction Therapy If unacceptable toxicity is seen in Phase I, Cohort 1, 12 additional subjects will be enrolled in Phase I, Cohort 2. Subjects will be treated with carboplatin AUC 6 given IV on Day 1 and nabpaclitaxel 100 mg/m2 given IV on Days 1, 8, and 15. Pembrolizumab 2\* mg/kg IV will be given on Day 1 starting in cycle 2. Treatment will continue for a maximum duration of 4 cycles (pembrolizumab given Cycles 2 to 4 only).
Phase I: Overall Survival (OS)	13 months Interval 7.1 to 36.0	—

SECONDARY outcome

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

To evaluate overall survival rates for phase II participants receiving MK-3475 and carboplatin/nab-paclitaxel for the first line treatment of advanced NSCLC.

Outcome measures

Outcome measures
Measure	Phase I, Cohort 1 n=32 Participants Phase I, Cohort 1: Induction Therapy Twelve subjects will be enrolled to Cohort 1 and treated with carboplatin AUC 6 IV on Day 1, nab-paclitaxel 100 mg/m\^2 given IV on Days 1, 8, and 15, and pembrolizumab 2\* mg/kg IV on Day 1.Treatment will continue for a maximum duration of 4 cycles with cycle length of 21 days. Phase I, Cohort 1 Maintenance Therapy: Participants who have confirmed CR, PR, or SD (non-progression) after 4 cycles, maintenance therapy with pembrolizumab 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.	Phase I, Cohort 2 Phase I, Cohort 2: Induction Therapy If unacceptable toxicity is seen in Phase I, Cohort 1, 12 additional subjects will be enrolled in Phase I, Cohort 2. Subjects will be treated with carboplatin AUC 6 given IV on Day 1 and nabpaclitaxel 100 mg/m2 given IV on Days 1, 8, and 15. Pembrolizumab 2\* mg/kg IV will be given on Day 1 starting in cycle 2. Treatment will continue for a maximum duration of 4 cycles (pembrolizumab given Cycles 2 to 4 only).
Phase II: Overall Survival (OS)	16 months Interval 12.0 to upper limit has not been achieved due to insufficient number of participants with events.	—

SECONDARY outcome

To evaluate anti-tumor activity for phase I participants will be reported as a percentage change in the sum of the dimensions of all measurable lesions as defined by RECIST 1.1 criteria.

Outcome measures

Outcome measures
Measure	Phase I, Cohort 1 n=32 Participants Phase I, Cohort 1: Induction Therapy Twelve subjects will be enrolled to Cohort 1 and treated with carboplatin AUC 6 IV on Day 1, nab-paclitaxel 100 mg/m\^2 given IV on Days 1, 8, and 15, and pembrolizumab 2\* mg/kg IV on Day 1.Treatment will continue for a maximum duration of 4 cycles with cycle length of 21 days. Phase I, Cohort 1 Maintenance Therapy: Participants who have confirmed CR, PR, or SD (non-progression) after 4 cycles, maintenance therapy with pembrolizumab 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.	Phase I, Cohort 2 Phase I, Cohort 2: Induction Therapy If unacceptable toxicity is seen in Phase I, Cohort 1, 12 additional subjects will be enrolled in Phase I, Cohort 2. Subjects will be treated with carboplatin AUC 6 given IV on Day 1 and nabpaclitaxel 100 mg/m2 given IV on Days 1, 8, and 15. Pembrolizumab 2\* mg/kg IV will be given on Day 1 starting in cycle 2. Treatment will continue for a maximum duration of 4 cycles (pembrolizumab given Cycles 2 to 4 only).
Phase II: Disease Assessment for Anti-Tumor Activity	-46.7731 percent change Interval -51.7 to -35.1	—

SECONDARY outcome

Timeframe: 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. Safety and tolerability is defined as rates of Grade 1-5 toxicity according to CTCAE v4.

Outcome measures

Outcome measures
Measure	Phase I, Cohort 1 n=32 Participants Phase I, Cohort 1: Induction Therapy Twelve subjects will be enrolled to Cohort 1 and treated with carboplatin AUC 6 IV on Day 1, nab-paclitaxel 100 mg/m\^2 given IV on Days 1, 8, and 15, and pembrolizumab 2\* mg/kg IV on Day 1.Treatment will continue for a maximum duration of 4 cycles with cycle length of 21 days. Phase I, Cohort 1 Maintenance Therapy: Participants who have confirmed CR, PR, or SD (non-progression) after 4 cycles, maintenance therapy with pembrolizumab 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.	Phase I, Cohort 2 Phase I, Cohort 2: Induction Therapy If unacceptable toxicity is seen in Phase I, Cohort 1, 12 additional subjects will be enrolled in Phase I, Cohort 2. Subjects will be treated with carboplatin AUC 6 given IV on Day 1 and nabpaclitaxel 100 mg/m2 given IV on Days 1, 8, and 15. Pembrolizumab 2\* mg/kg IV will be given on Day 1 starting in cycle 2. Treatment will continue for a maximum duration of 4 cycles (pembrolizumab given Cycles 2 to 4 only).
Phase II: Number of Participants With Adverse Events as a Measure of Safety and Tolerability Patient having serious adverse event.	11 Participants	—
Phase II: Number of Participants With Adverse Events as a Measure of Safety and Tolerability Patient had at least one adverse event of any grade.	32 Participants	—
Phase II: Number of Participants With Adverse Events as a Measure of Safety and Tolerability Patient had at least one grade 3 or greater adverse event.	31 Participants	—
Phase II: Number of Participants With Adverse Events as a Measure of Safety and Tolerability Patient had at least one grade 3 or greater treatment related adverse event.	27 Participants	—

SECONDARY outcome

Population: 34 of the 46 subjects have staining information available

To evaluate the association of PD-L1 expression on PFS for all 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.

Outcome measures

Outcome measures
Measure	Phase I, Cohort 1 n=34 Participants Phase I, Cohort 1: Induction Therapy Twelve subjects will be enrolled to Cohort 1 and treated with carboplatin AUC 6 IV on Day 1, nab-paclitaxel 100 mg/m\^2 given IV on Days 1, 8, and 15, and pembrolizumab 2\* mg/kg IV on Day 1.Treatment will continue for a maximum duration of 4 cycles with cycle length of 21 days. Phase I, Cohort 1 Maintenance Therapy: Participants who have confirmed CR, PR, or SD (non-progression) after 4 cycles, maintenance therapy with pembrolizumab 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.	Phase I, Cohort 2 Phase I, Cohort 2: Induction Therapy If unacceptable toxicity is seen in Phase I, Cohort 1, 12 additional subjects will be enrolled in Phase I, Cohort 2. Subjects will be treated with carboplatin AUC 6 given IV on Day 1 and nabpaclitaxel 100 mg/m2 given IV on Days 1, 8, and 15. Pembrolizumab 2\* mg/kg IV will be given on Day 1 starting in cycle 2. Treatment will continue for a maximum duration of 4 cycles (pembrolizumab given Cycles 2 to 4 only).
All Phases: Assessment of Association of PD-L1 Expression on PFS 0%	5.6 months Interval 3.9 to upper limit has not been achieved due to insufficient number of participants with events.	—
All Phases: Assessment of Association of PD-L1 Expression on PFS >=50%	4.6 months Interval 2.9 to upper limit has not been achieved due to insufficient number of participants with events.	—
All Phases: Assessment of Association of PD-L1 Expression on PFS 0-49%	4.2 months Interval 3.9 to upper limit has not been achieved due to insufficient number of participants with events.	—

Adverse Events

Phase I, Cohort 1

Serious events: 8 serious events

Other events: 14 other events

Deaths: 11 deaths

Phase I, Cohort 2

Serious events: 0 serious events

Other events: 0 other events

Deaths: 0 deaths

Phase II

Serious events: 11 serious events

Other events: 32 other events

Deaths: 19 deaths

Serious adverse events

Other adverse events

Additional Information

Annesha Majumdar

Hoosier Cancer Research Network

Phone: 3179212050

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Measure	Phase I, Cohort 1 n=14 participants at risk Phase I, Cohort 1: Induction Therapy Twelve subjects will be enrolled to Cohort 1 and treated with carboplatin AUC 6 IV on Day 1, nab-paclitaxel 100 mg/m\^2 given IV on Days 1, 8, and 15, and pembrolizumab 2\* mg/kg IV on Day 1.Treatment will continue for a maximum duration of 4 cycles with cycle length of 21 days. Phase I, Cohort 1 Maintenance Therapy: Participants who have confirmed CR, PR, or SD (non-progression) after 4 cycles, maintenance therapy with pembrolizumab 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.	Phase I, Cohort 2 Phase I, Cohort 2: Induction Therapy If unacceptable toxicity is seen in Phase I, Cohort 1, 12 additional subjects will be enrolled in Phase I, Cohort 2. Subjects will be treated with carboplatin AUC 6 given IV on Day 1 and nabpaclitaxel 100 mg/m2 given IV on Days 1, 8, and 15. Pembrolizumab 2\* mg/kg IV will be given on Day 1 starting in cycle 2. Treatment will continue for a maximum duration of 4 cycles (pembrolizumab given Cycles 2 to 4 only). 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.	Phase II n=32 participants at risk Induction Therapy Cycles 1-4 Subjects will be treated with carboplatin AUC 6 given IV on Day 1, nab-paclitaxel 100 mg/m2 given IV on Days 1, 8, and 15, and pembrolizumab 200 mg IV on Day 1. Treatment will continue for a maximum duration of 4 cycles of study treatment. Each cycle starts when all the criteria to start a new cycle are met. A cycle is defined only when you can give all 3 drugs on Day 1, and it coincides with pembrolizumab. Pembrolizumab should be given with carboplatin and nab-paclitaxel on day 1 of the cycle. Chemotherapies may be withheld for six weeks, while pembrolizumab can be withheld for 12-weeks. If there is a pembrolizumab-specific toxicity requiring pembrolizumab to be held, chemotherapy should be resumed without pembrolizumab within 6 weeks if it is felt that chemotherapy is safe by the site investigator. Delays in chemotherapy beyond 6 weeks require withdrawal from the study treatment. 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.
Renal and urinary disorders ACUTE KIDNEY INJURY	7.1% 1/14 • Number of events 1 • Begin C1D1 and every 2 chemotherapy cycles (6 weeks) thereafter, for up to 2 years or until unacceptable toxicity. No subjects had been enrolled in Phase 1 Cohort 2.	— 0/0 • Begin C1D1 and every 2 chemotherapy cycles (6 weeks) thereafter, for up to 2 years or until unacceptable toxicity. No subjects had been enrolled in Phase 1 Cohort 2.	3.1% 1/32 • Number of events 1 • Begin C1D1 and every 2 chemotherapy cycles (6 weeks) thereafter, for up to 2 years or until unacceptable toxicity. No subjects had been enrolled in Phase 1 Cohort 2.
Blood and lymphatic system disorders ANEMIA	7.1% 1/14 • Number of events 1 • Begin C1D1 and every 2 chemotherapy cycles (6 weeks) thereafter, for up to 2 years or until unacceptable toxicity. No subjects had been enrolled in Phase 1 Cohort 2.	— 0/0 • Begin C1D1 and every 2 chemotherapy cycles (6 weeks) thereafter, for up to 2 years or until unacceptable toxicity. No subjects had been enrolled in Phase 1 Cohort 2.	0.00% 0/32 • Begin C1D1 and every 2 chemotherapy cycles (6 weeks) thereafter, for up to 2 years or until unacceptable toxicity. No subjects had been enrolled in Phase 1 Cohort 2.
Cardiac disorders ATRIAL FLUTTER	7.1% 1/14 • Number of events 1 • Begin C1D1 and every 2 chemotherapy cycles (6 weeks) thereafter, for up to 2 years or until unacceptable toxicity. No subjects had been enrolled in Phase 1 Cohort 2.	— 0/0 • Begin C1D1 and every 2 chemotherapy cycles (6 weeks) thereafter, for up to 2 years or until unacceptable toxicity. No subjects had been enrolled in Phase 1 Cohort 2.	3.1% 1/32 • Number of events 1 • Begin C1D1 and every 2 chemotherapy cycles (6 weeks) thereafter, for up to 2 years or until unacceptable toxicity. No subjects had been enrolled in Phase 1 Cohort 2.
Musculoskeletal and connective tissue disorders BACK PAIN	7.1% 1/14 • Number of events 1 • Begin C1D1 and every 2 chemotherapy cycles (6 weeks) thereafter, for up to 2 years or until unacceptable toxicity. No subjects had been enrolled in Phase 1 Cohort 2.	— 0/0 • Begin C1D1 and every 2 chemotherapy cycles (6 weeks) thereafter, for up to 2 years or until unacceptable toxicity. No subjects had been enrolled in Phase 1 Cohort 2.	0.00% 0/32 • Begin C1D1 and every 2 chemotherapy cycles (6 weeks) thereafter, for up to 2 years or until unacceptable toxicity. No subjects had been enrolled in Phase 1 Cohort 2.
Metabolism and nutrition disorders DEHYDRATION	7.1% 1/14 • Number of events 1 • Begin C1D1 and every 2 chemotherapy cycles (6 weeks) thereafter, for up to 2 years or until unacceptable toxicity. No subjects had been enrolled in Phase 1 Cohort 2.	— 0/0 • Begin C1D1 and every 2 chemotherapy cycles (6 weeks) thereafter, for up to 2 years or until unacceptable toxicity. No subjects had been enrolled in Phase 1 Cohort 2.	0.00% 0/32 • Begin C1D1 and every 2 chemotherapy cycles (6 weeks) thereafter, for up to 2 years or until unacceptable toxicity. No subjects had been enrolled in Phase 1 Cohort 2.
Blood and lymphatic system disorders FEBRILE NEUTROPENIA	7.1% 1/14 • Number of events 1 • Begin C1D1 and every 2 chemotherapy cycles (6 weeks) thereafter, for up to 2 years or until unacceptable toxicity. No subjects had been enrolled in Phase 1 Cohort 2.	— 0/0 • Begin C1D1 and every 2 chemotherapy cycles (6 weeks) thereafter, for up to 2 years or until unacceptable toxicity. No subjects had been enrolled in Phase 1 Cohort 2.	3.1% 1/32 • Number of events 1 • Begin C1D1 and every 2 chemotherapy cycles (6 weeks) thereafter, for up to 2 years or until unacceptable toxicity. No subjects had been enrolled in Phase 1 Cohort 2.
General disorders GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS	7.1% 1/14 • Number of events 1 • Begin C1D1 and every 2 chemotherapy cycles (6 weeks) thereafter, for up to 2 years or until unacceptable toxicity. No subjects had been enrolled in Phase 1 Cohort 2.	— 0/0 • Begin C1D1 and every 2 chemotherapy cycles (6 weeks) thereafter, for up to 2 years or until unacceptable toxicity. No subjects had been enrolled in Phase 1 Cohort 2.	0.00% 0/32 • Begin C1D1 and every 2 chemotherapy cycles (6 weeks) thereafter, for up to 2 years or until unacceptable toxicity. No subjects had been enrolled in Phase 1 Cohort 2.
Nervous system disorders HEADACHE	7.1% 1/14 • Number of events 1 • Begin C1D1 and every 2 chemotherapy cycles (6 weeks) thereafter, for up to 2 years or until unacceptable toxicity. No subjects had been enrolled in Phase 1 Cohort 2.	— 0/0 • Begin C1D1 and every 2 chemotherapy cycles (6 weeks) thereafter, for up to 2 years or until unacceptable toxicity. No subjects had been enrolled in Phase 1 Cohort 2.	0.00% 0/32 • Begin C1D1 and every 2 chemotherapy cycles (6 weeks) thereafter, for up to 2 years or until unacceptable toxicity. No subjects had been enrolled in Phase 1 Cohort 2.
Gastrointestinal disorders HEMORRHOIDAL HEMORRHAGE	7.1% 1/14 • Number of events 1 • Begin C1D1 and every 2 chemotherapy cycles (6 weeks) thereafter, for up to 2 years or until unacceptable toxicity. No subjects had been enrolled in Phase 1 Cohort 2.	— 0/0 • Begin C1D1 and every 2 chemotherapy cycles (6 weeks) thereafter, for up to 2 years or until unacceptable toxicity. No subjects had been enrolled in Phase 1 Cohort 2.	0.00% 0/32 • Begin C1D1 and every 2 chemotherapy cycles (6 weeks) thereafter, for up to 2 years or until unacceptable toxicity. No subjects had been enrolled in Phase 1 Cohort 2.
Metabolism and nutrition disorders HYPERGLYCEMIA	7.1% 1/14 • Number of events 1 • Begin C1D1 and every 2 chemotherapy cycles (6 weeks) thereafter, for up to 2 years or until unacceptable toxicity. No subjects had been enrolled in Phase 1 Cohort 2.	— 0/0 • Begin C1D1 and every 2 chemotherapy cycles (6 weeks) thereafter, for up to 2 years or until unacceptable toxicity. No subjects had been enrolled in Phase 1 Cohort 2.	0.00% 0/32 • Begin C1D1 and every 2 chemotherapy cycles (6 weeks) thereafter, for up to 2 years or until unacceptable toxicity. No subjects had been enrolled in Phase 1 Cohort 2.
Gastrointestinal disorders INTRA-ABDOMINAL HEMORRHAGE	7.1% 1/14 • Number of events 1 • Begin C1D1 and every 2 chemotherapy cycles (6 weeks) thereafter, for up to 2 years or until unacceptable toxicity. No subjects had been enrolled in Phase 1 Cohort 2.	— 0/0 • Begin C1D1 and every 2 chemotherapy cycles (6 weeks) thereafter, for up to 2 years or until unacceptable toxicity. No subjects had been enrolled in Phase 1 Cohort 2.	0.00% 0/32 • Begin C1D1 and every 2 chemotherapy cycles (6 weeks) thereafter, for up to 2 years or until unacceptable toxicity. No subjects had been enrolled in Phase 1 Cohort 2.
Metabolism and nutrition disorders METABOLISM AND NUTRITION DISORDERS	7.1% 1/14 • Number of events 1 • Begin C1D1 and every 2 chemotherapy cycles (6 weeks) thereafter, for up to 2 years or until unacceptable toxicity. No subjects had been enrolled in Phase 1 Cohort 2.	— 0/0 • Begin C1D1 and every 2 chemotherapy cycles (6 weeks) thereafter, for up to 2 years or until unacceptable toxicity. No subjects had been enrolled in Phase 1 Cohort 2.	0.00% 0/32 • Begin C1D1 and every 2 chemotherapy cycles (6 weeks) thereafter, for up to 2 years or until unacceptable toxicity. No subjects had been enrolled in Phase 1 Cohort 2.
Musculoskeletal and connective tissue disorders MUSCLE WEAKNESS LOWER LIMB	7.1% 1/14 • Number of events 1 • Begin C1D1 and every 2 chemotherapy cycles (6 weeks) thereafter, for up to 2 years or until unacceptable toxicity. No subjects had been enrolled in Phase 1 Cohort 2.	— 0/0 • Begin C1D1 and every 2 chemotherapy cycles (6 weeks) thereafter, for up to 2 years or until unacceptable toxicity. No subjects had been enrolled in Phase 1 Cohort 2.	0.00% 0/32 • Begin C1D1 and every 2 chemotherapy cycles (6 weeks) thereafter, for up to 2 years or until unacceptable toxicity. No subjects had been enrolled in Phase 1 Cohort 2.
General disorders PAIN	7.1% 1/14 • Number of events 1 • Begin C1D1 and every 2 chemotherapy cycles (6 weeks) thereafter, for up to 2 years or until unacceptable toxicity. No subjects had been enrolled in Phase 1 Cohort 2.	— 0/0 • Begin C1D1 and every 2 chemotherapy cycles (6 weeks) thereafter, for up to 2 years or until unacceptable toxicity. No subjects had been enrolled in Phase 1 Cohort 2.	0.00% 0/32 • Begin C1D1 and every 2 chemotherapy cycles (6 weeks) thereafter, for up to 2 years or until unacceptable toxicity. No subjects had been enrolled in Phase 1 Cohort 2.
Renal and urinary disorders RENAL AND URINARY DISORDERS	7.1% 1/14 • Number of events 1 • Begin C1D1 and every 2 chemotherapy cycles (6 weeks) thereafter, for up to 2 years or until unacceptable toxicity. No subjects had been enrolled in Phase 1 Cohort 2.	— 0/0 • Begin C1D1 and every 2 chemotherapy cycles (6 weeks) thereafter, for up to 2 years or until unacceptable toxicity. No subjects had been enrolled in Phase 1 Cohort 2.	0.00% 0/32 • Begin C1D1 and every 2 chemotherapy cycles (6 weeks) thereafter, for up to 2 years or until unacceptable toxicity. No subjects had been enrolled in Phase 1 Cohort 2.
Respiratory, thoracic and mediastinal disorders RESPIRATORY FAILURE	7.1% 1/14 • Number of events 1 • Begin C1D1 and every 2 chemotherapy cycles (6 weeks) thereafter, for up to 2 years or until unacceptable toxicity. No subjects had been enrolled in Phase 1 Cohort 2.	— 0/0 • Begin C1D1 and every 2 chemotherapy cycles (6 weeks) thereafter, for up to 2 years or until unacceptable toxicity. No subjects had been enrolled in Phase 1 Cohort 2.	0.00% 0/32 • Begin C1D1 and every 2 chemotherapy cycles (6 weeks) thereafter, for up to 2 years or until unacceptable toxicity. No subjects had been enrolled in Phase 1 Cohort 2.
Respiratory, thoracic and mediastinal disorders RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS	7.1% 1/14 • Number of events 1 • Begin C1D1 and every 2 chemotherapy cycles (6 weeks) thereafter, for up to 2 years or until unacceptable toxicity. No subjects had been enrolled in Phase 1 Cohort 2.	— 0/0 • Begin C1D1 and every 2 chemotherapy cycles (6 weeks) thereafter, for up to 2 years or until unacceptable toxicity. No subjects had been enrolled in Phase 1 Cohort 2.	0.00% 0/32 • Begin C1D1 and every 2 chemotherapy cycles (6 weeks) thereafter, for up to 2 years or until unacceptable toxicity. No subjects had been enrolled in Phase 1 Cohort 2.
Vascular disorders THROMBOEMBOLIC EVENT	7.1% 1/14 • Number of events 1 • Begin C1D1 and every 2 chemotherapy cycles (6 weeks) thereafter, for up to 2 years or until unacceptable toxicity. No subjects had been enrolled in Phase 1 Cohort 2.	— 0/0 • Begin C1D1 and every 2 chemotherapy cycles (6 weeks) thereafter, for up to 2 years or until unacceptable toxicity. No subjects had been enrolled in Phase 1 Cohort 2.	3.1% 1/32 • Number of events 1 • Begin C1D1 and every 2 chemotherapy cycles (6 weeks) thereafter, for up to 2 years or until unacceptable toxicity. No subjects had been enrolled in Phase 1 Cohort 2.
Cardiac disorders CARDIAC ARREST	0.00% 0/14 • Begin C1D1 and every 2 chemotherapy cycles (6 weeks) thereafter, for up to 2 years or until unacceptable toxicity. No subjects had been enrolled in Phase 1 Cohort 2.	— 0/0 • Begin C1D1 and every 2 chemotherapy cycles (6 weeks) thereafter, for up to 2 years or until unacceptable toxicity. No subjects had been enrolled in Phase 1 Cohort 2.	3.1% 1/32 • Number of events 1 • Begin C1D1 and every 2 chemotherapy cycles (6 weeks) thereafter, for up to 2 years or until unacceptable toxicity. No subjects had been enrolled in Phase 1 Cohort 2.
Psychiatric disorders CONFUSION	0.00% 0/14 • Begin C1D1 and every 2 chemotherapy cycles (6 weeks) thereafter, for up to 2 years or until unacceptable toxicity. No subjects had been enrolled in Phase 1 Cohort 2.	— 0/0 • Begin C1D1 and every 2 chemotherapy cycles (6 weeks) thereafter, for up to 2 years or until unacceptable toxicity. No subjects had been enrolled in Phase 1 Cohort 2.	3.1% 1/32 • Number of events 1 • Begin C1D1 and every 2 chemotherapy cycles (6 weeks) thereafter, for up to 2 years or until unacceptable toxicity. No subjects had been enrolled in Phase 1 Cohort 2.
General disorders DEATH NOS	0.00% 0/14 • Begin C1D1 and every 2 chemotherapy cycles (6 weeks) thereafter, for up to 2 years or until unacceptable toxicity. No subjects had been enrolled in Phase 1 Cohort 2.	— 0/0 • Begin C1D1 and every 2 chemotherapy cycles (6 weeks) thereafter, for up to 2 years or until unacceptable toxicity. No subjects had been enrolled in Phase 1 Cohort 2.	3.1% 1/32 • Number of events 1 • Begin C1D1 and every 2 chemotherapy cycles (6 weeks) thereafter, for up to 2 years or until unacceptable toxicity. No subjects had been enrolled in Phase 1 Cohort 2.
Gastrointestinal disorders DIARRHEA	0.00% 0/14 • Begin C1D1 and every 2 chemotherapy cycles (6 weeks) thereafter, for up to 2 years or until unacceptable toxicity. No subjects had been enrolled in Phase 1 Cohort 2.	— 0/0 • Begin C1D1 and every 2 chemotherapy cycles (6 weeks) thereafter, for up to 2 years or until unacceptable toxicity. No subjects had been enrolled in Phase 1 Cohort 2.	3.1% 1/32 • Number of events 2 • Begin C1D1 and every 2 chemotherapy cycles (6 weeks) thereafter, for up to 2 years or until unacceptable toxicity. No subjects had been enrolled in Phase 1 Cohort 2.
General disorders EDEMA LIMBS	0.00% 0/14 • Begin C1D1 and every 2 chemotherapy cycles (6 weeks) thereafter, for up to 2 years or until unacceptable toxicity. No subjects had been enrolled in Phase 1 Cohort 2.	— 0/0 • Begin C1D1 and every 2 chemotherapy cycles (6 weeks) thereafter, for up to 2 years or until unacceptable toxicity. No subjects had been enrolled in Phase 1 Cohort 2.	3.1% 1/32 • Number of events 1 • Begin C1D1 and every 2 chemotherapy cycles (6 weeks) thereafter, for up to 2 years or until unacceptable toxicity. No subjects had been enrolled in Phase 1 Cohort 2.
Injury, poisoning and procedural complications HIP FRACTURE	0.00% 0/14 • Begin C1D1 and every 2 chemotherapy cycles (6 weeks) thereafter, for up to 2 years or until unacceptable toxicity. No subjects had been enrolled in Phase 1 Cohort 2.	— 0/0 • Begin C1D1 and every 2 chemotherapy cycles (6 weeks) thereafter, for up to 2 years or until unacceptable toxicity. No subjects had been enrolled in Phase 1 Cohort 2.	3.1% 1/32 • Number of events 1 • Begin C1D1 and every 2 chemotherapy cycles (6 weeks) thereafter, for up to 2 years or until unacceptable toxicity. No subjects had been enrolled in Phase 1 Cohort 2.
Gastrointestinal disorders ILEAL OBSTRUCTION	0.00% 0/14 • Begin C1D1 and every 2 chemotherapy cycles (6 weeks) thereafter, for up to 2 years or until unacceptable toxicity. No subjects had been enrolled in Phase 1 Cohort 2.	— 0/0 • Begin C1D1 and every 2 chemotherapy cycles (6 weeks) thereafter, for up to 2 years or until unacceptable toxicity. No subjects had been enrolled in Phase 1 Cohort 2.	3.1% 1/32 • Number of events 3 • Begin C1D1 and every 2 chemotherapy cycles (6 weeks) thereafter, for up to 2 years or until unacceptable toxicity. No subjects had been enrolled in Phase 1 Cohort 2.
Infections and infestations LUNG INFECTION	0.00% 0/14 • Begin C1D1 and every 2 chemotherapy cycles (6 weeks) thereafter, for up to 2 years or until unacceptable toxicity. No subjects had been enrolled in Phase 1 Cohort 2.	— 0/0 • Begin C1D1 and every 2 chemotherapy cycles (6 weeks) thereafter, for up to 2 years or until unacceptable toxicity. No subjects had been enrolled in Phase 1 Cohort 2.	6.2% 2/32 • Number of events 2 • Begin C1D1 and every 2 chemotherapy cycles (6 weeks) thereafter, for up to 2 years or until unacceptable toxicity. No subjects had been enrolled in Phase 1 Cohort 2.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS)	0.00% 0/14 • Begin C1D1 and every 2 chemotherapy cycles (6 weeks) thereafter, for up to 2 years or until unacceptable toxicity. No subjects had been enrolled in Phase 1 Cohort 2.	— 0/0 • Begin C1D1 and every 2 chemotherapy cycles (6 weeks) thereafter, for up to 2 years or until unacceptable toxicity. No subjects had been enrolled in Phase 1 Cohort 2.	3.1% 1/32 • Number of events 1 • Begin C1D1 and every 2 chemotherapy cycles (6 weeks) thereafter, for up to 2 years or until unacceptable toxicity. No subjects had been enrolled in Phase 1 Cohort 2.
Respiratory, thoracic and mediastinal disorders PLEURAL EFFUSION	0.00% 0/14 • Begin C1D1 and every 2 chemotherapy cycles (6 weeks) thereafter, for up to 2 years or until unacceptable toxicity. No subjects had been enrolled in Phase 1 Cohort 2.	— 0/0 • Begin C1D1 and every 2 chemotherapy cycles (6 weeks) thereafter, for up to 2 years or until unacceptable toxicity. No subjects had been enrolled in Phase 1 Cohort 2.	3.1% 1/32 • Number of events 1 • Begin C1D1 and every 2 chemotherapy cycles (6 weeks) thereafter, for up to 2 years or until unacceptable toxicity. No subjects had been enrolled in Phase 1 Cohort 2.
Infections and infestations SEPSIS	0.00% 0/14 • Begin C1D1 and every 2 chemotherapy cycles (6 weeks) thereafter, for up to 2 years or until unacceptable toxicity. No subjects had been enrolled in Phase 1 Cohort 2.	— 0/0 • Begin C1D1 and every 2 chemotherapy cycles (6 weeks) thereafter, for up to 2 years or until unacceptable toxicity. No subjects had been enrolled in Phase 1 Cohort 2.	6.2% 2/32 • Number of events 2 • Begin C1D1 and every 2 chemotherapy cycles (6 weeks) thereafter, for up to 2 years or until unacceptable toxicity. No subjects had been enrolled in Phase 1 Cohort 2.