Safety and Efficacy Study of Pembrolizumab (MK-3475) in Combination With Chemotherapy as Neoadjuvant Treatment for Participants With Triple Negative Breast Cancer (TNBC) (MK-3475-173/KEYNOTE-173)

Conditions

Triple Negative Breast Neoplasms

Keywords

Programmed Cell Death-1 (PD1, PD-1), Programmed Death-Ligand 1 (PDL1, PD-L1), Triple Negative Breast Cancer

Brief summary

The purpose of this study is to evaluate the safety, tolerability and clinical activity of pembrolizumab (MK-3475) in combination with six chemotherapy regimens as neoadjuvant treatment for participants with triple negative breast cancer (TNBC).

Dent R, Cortés J, Park YH, Muñoz-Couselo E, Kim SB, Sohn J, Im SA, Holgado E, Foukakis T, Kümmel S, Yearley J, Wang A, Nebozhyn M, Huang L, Cristescu R, Jelinic P, Karantza V, Schmid P.

2025-03-112 citations

10.1186/s13058-024-01946-y

338 Effects of pembrolizumab on the tumor microenvironment (TME) after one presurgery treatment cycle in patients with triple-negative breast cancer (TNBC): phase 1b KEYNOTE-173 study

Peter Schmid, Yeon Hee Park, Eva Muñoz‐Couselo, Sung‐Bae Kim, Joohyuk Sohn et al. (16 authors)

Regular and Young Investigator Award Abstracts2021-11-012 citations

10.1136/jitc-2021-sitc2021.338

Pembrolizumab plus chemotherapy as neoadjuvant treatment of high-risk, early-stage triple-negative breast cancer: results from the phase 1b open-label, multicohort KEYNOTE-173 study.

Schmid P, Salgado R, Park YH, Muñoz-Couselo E, Kim SB, Sohn J, Im SA, Foukakis T, Kuemmel S, Dent R, Yin L, Wang A, Tryfonidis K, Karantza V, Cortés J, Loi S.

2020-02-14296 citations

10.1016/j.annonc.2020.01.072

Abstract PD5-01: KEYNOTE-173: Phase 1b multicohort study of pembrolizumab (Pembro) in combination with chemotherapy as neoadjuvant treatment for triple-negative breast cancer (TNBC)

Peter Schmid, YH Park, Eva Muñoz‐Couselo, S-B. Kim, Joohyuk Sohn et al. (14 authors)

Cancer Research2019-02-1517 citations

10.1158/1538-7445.sabcs18-pd5-01

Abstract P3-10-09: Relationship between tumor infiltrating lymphocytes (TILs) and response to pembrolizumab (Pembro)+chemotherapy (Chemo) as neoadjuvant treatment (NAT) for triple-negative breast cancer (TNBC): phase Ib KEYNOTE-173 trial

Sherene Loi, Peter Schmid, Javier Cortés, YH Park, Eva Muñoz‐Couselo et al. (16 authors)

Cancer Research2019-02-156 citations

10.1158/1538-7445.sabcs18-p3-10-09

Pembrolizumab (pembro) + chemotherapy (chemo) as neoadjuvant treatment for triple negative breast cancer (TNBC): Preliminary results from KEYNOTE-173.

Peter Schmid, Yeon Hee Park, Eva Muñoz‐Couselo, Sung‐Bae Kim, Joohyuk Sohn et al. (11 authors)

Journal of Clinical Oncology2017-05-2086 citations

10.1200/jco.2017.35.15_suppl.556

Interventions

BIOLOGICALPembrolizumab

200 mg administered Q3W as an IV infusion.

DRUGNab-paclitaxel

125 mg/m\^2 or 100 mg/m\^2 administered weekly as an IV infusion, according to allocation.

DRUGAnthracycline (doxorubicin)

60 mg/m\^2 administered Q3W as an IV injection.

DRUGCyclophosphamide

600 mg/m\^2 administered Q3W as an IV infusion.

DRUGCarboplatin

AUC 6 or AUC5 administered Q3W as an IV infusion, or AUC2 administered weekly as an IV infusion, according to allocation.

DRUGPaclitaxel

80 mg/m\^2 or 70 mg/m\^2 administered weekly as an IV infusion, according to allocation.

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

FEMALE

Age

18 Years to No maximum

Healthy volunteers

No

Inclusion criteria

* Has previously untreated, locally advanced TNBC. * Is able to provide 2 core needle biopsies from the primary tumor at screening to the central laboratory and agrees to have a core needle biopsy after single dose pembrolizumab treatment if tumor biopsy is feasible as judged by the investigator. * Has Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. * Has adequate organ function. * Females of childbearing potential must be willing to use adequate contraception for the course of the study through 12 months after the last dose of study drug for participants receiving cyclophosphamide and through 6 months after the last dose of study drug for participants who do not receive cyclophosphamide.

Exclusion criteria

* Has evidence of metastatic breast cancer, concurrent bilateral invasive breast cancer, or inflammatory breast cancer. * Has another malignancy within the last 5 years. Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin that has undergone potentially curative surgery, or in situ cervical cancer. * Has received prior chemotherapy, targeted therapy, radiation therapy, immunotherapy that targets immune checkpoints, co-stimulatory or co-inhibitory pathways for T cell receptors within the past 12 months. * Is currently participating and receiving study therapy, or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks of the first dose of study drug. * Has received a live vaccine within 30 days of the first dose of study drug. * Has an active autoimmune disease that has required systemic treatment in past 2 years. * Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of study drug. * Has a known history of Human Immunodeficiency Virus (HIV). * Has known active Hepatitis B or Hepatitis C. * Has evidence of current pneumonitis. * Has a history of non-infectious pneumonitis requiring treatment with steroids or a history of interstitial lung disease. * Has an active infection requiring systemic therapy. * Has significant cardiovascular disease, such as: History of myocardial infarction, acute coronary syndrome or coronary angioplasty/stenting/bypass grafting within the last 6 months; Congestive heart failure (CHF) New York Heart Association (NYHA) Class II-IV or history of CHF NYHA class III or IV * Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the study. * Is pregnant or breastfeeding, or expecting to conceive children within the projected duration of the study, starting with the screening visit through 12 months after the last dose of trial treatment for participants who have received cyclophosphamide, and for six months after the last dose of study medication for participants who have not. * Has a known hypersensitivity to the components of the study drug or its analogs.

Design outcomes

Primary

Measure	Time frame	Description
Number of Participants With Dose Limiting Toxicities (DLTs) Graded Using National Cancer Institute Common Toxicity Criteria for Adverse Events Version 4.0 (NCI CTCAE v4.0)	Cycle 1 Day 1 through end of Cycle 3 and Cycle 6 Day 1 through end of Cycle 7 (Up to ~150 days from first dose of first combination regimen); Each cycle was 21 days.	The following events, if considered to be study-treatment-related by the Investigator, were considered a DLT: * Hematologic: * Grade 4 neutropenia lasting ≥8 days; * Febrile neutropenia Grade 3 or Grade 4; or * Grade 4 thrombocytopenia requiring platelet transfusion, or Grade 3 thrombocytopenia with bleeding * Non-hematologic: * Grade 4 toxicity; * Grade ≥3 symptomatic hepatic toxicities lasting \>48 hours, or Grade ≥3 asymptomatic hepatic toxicities lasting ≥7 days; or * Grade ≥3 non-hematologic, non-hepatic organ toxicity, with exceptions * Other: * Any treatment delays for ≥14 days due to unresolved toxicity; * Grade 5 treatment-related adverse event (AE); * A dose reduction of study treatment during the DLT evaluation period.
Number of Participants Who Experienced an Adverse Event (AE)	Up to approximately 28 months (through Interim database cut-off date of 31-May-2018)	An AE was defined as any untoward medical occurrence in a participant administered study treatment and which does not necessarily have to have a causal relationship with this treatment. The number of participants who experienced an AE either prior to or after definitive surgery is presented.
Number of Participants Who Discontinued Study Treatment Due to an Adverse Event (AE)	Up to approximately 28 months (through Interim database cut-off date of 31-May-2018)	An AE was defined as any untoward medical occurrence in a participant administered study treatment and which does not necessarily have to have a causal relationship with this treatment. The number of participants who discontinued study treatment due to an AE is presented.

Secondary

Measure	Time frame	Description
Objective Response Rate (ORR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Investigator Review: Second Combination Regimen	After completion of the second combination regimen (KAC; Cycle 9) but prior to surgery (Up to ~9 months); Each cycle was 21 days.	ORR was defined as the percentage of participants who achieved a complete response (CR: disappearance of all target lesions) or partial response (PR: at least a 30% decrease in the sum of diameters \[SOD\] of target lesions) according to RECIST 1.1 by Investigator review. Because imaging was assessed prior to surgery, a confirmation assessment of CR or PR was not obtained. Participants with missing outcome for objective response were considered non-responders. The percentage of participants who experienced a CR or PR based on RECIST 1.1 following the second combination regimen is presented.
Event-Free Survival (EFS) Rate at Month 6	Month 6	EFS was defined as the time from the first dose date of study treatment to any of the following events: progression of disease that precludes definitive surgery, disease recurrence (for participants with complete surgical resection), progression (for participants with incomplete surgical resection), or death due to any cause. Participants without documented events were censored at the date of the last disease status assessment. The Kaplan-Meier estimates of the percentage of participants who were event free at Month 6 are presented (through Final Analysis cut-off of 18-Nov-2019).
Event-Free Survival (EFS) Rate at Month 12	Month 12	EFS was defined as the time from the first dose date of study treatment to any of the following events: progression of disease that precludes definitive surgery, disease recurrence (for participants with complete surgical resection), progression (for participants with incomplete surgical resection), or death due to any cause. Participants without documented events were censored at the date of the last disease status assessment. The Kaplan-Meier estimates of the percentage of participants who were event free at Month 12 are presented (through Final Analysis cut-off of 18-Nov-2019).
Pathological Complete Response (pCR) Rate Using the Definition of ypT0 ypN0 (No Invasive or Noninvasive Residual in Breast or Nodes)	Up to approximately 9 months (at the time of definitive surgery)	pCR rate (ypT0 ypN0; no invasive or noninvasive residual in breast or nodes) was defined as the rate of absence of residual invasive and in situ cancer on hematoxylin and eosin evaluation of the complete resected breast specimen and all sampled regional lymph nodes following completion of neoadjuvant systemic therapy by American Joint Committee on Cancer (AJCC) staging criteria assessed by local pathologist at the time of definitive surgery. The percentage of participants with a pCR using the definition of ypT0 ypN0 is presented.
Overall Survival (OS) Rate at Month 6	Month 6	OS was defined as the time from the first dose date of study treatment to death due to any cause. Participants without documented death at the time of the analysis were censored at the date of the last follow-up. The Kaplan-Meier estimates of the percentage of participants who were surviving at Month 6 are presented (through Final Analysis cut-off of 18-Nov-2019).
Overall Survival (OS) Rate at Month 12	Month 12	OS was defined as the time from the first dose date of study treatment to death due to any cause. Participants without documented death at the time of the analysis were censored at the date of the last follow-up. The Kaplan-Meier estimates of the percentage of participants who were surviving at Month 12 are presented (through Final Analysis cut-off of 18-Nov-2019).
Overall Survival (OS) Rate at Month 24	Month 24	OS was defined as the time from the first dose date of study treatment to death due to any cause. Participants without documented death at the time of the analysis were censored at the date of the last follow-up. The Kaplan-Meier estimates of the percentage of participants who were surviving at Month 24 are presented (through Final Analysis cut-off of 18-Nov-2019).
Event-Free Survival (EFS) Rate at Month 24	Month 24	EFS was defined as the time from the first dose date of study treatment to any of the following events: progression of disease that precludes definitive surgery, disease recurrence (for participants with complete surgical resection), progression (for participants with incomplete surgical resection), or death due to any cause. Participants without documented events were censored at the date of the last disease status assessment. The Kaplan-Meier estimates of the percentage of participants who were event free at Month 24 are presented (through Final Analysis cut-off of 18-Nov-2019).
Pathological Complete Response (pCR) Rate Using the Definition of ypT0/Tis ypN0 (No Invasive Residual in Breast or Nodes; Noninvasive Breast Residuals Allowed)	Up to approximately 9 months (at the time of definitive surgery)	pCR rate (ypT0/Tis ypN0; no invasive residual in breast or nodes; noninvasive breast residuals allowed) was defined as the rate of absence of residual invasive cancer on hematoxylin and eosin evaluation of the complete resected breast specimen and all sampled regional lymph nodes following completion of neoadjuvant systemic therapy by AJCC staging criteria assessed by local pathologist at the time of definitive surgery. The percentage of participants with a pCR using the alternative definition of ypT0/Tis ypN0 is presented.
Objective Response Rate (ORR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Investigator Review: First Combination Regimen	At the end of Cycle 5 following treatment with the first combination regimen (KNp, KNpCb, or KTCb) (Up to ~4 months); Each cycle was 21 days.	ORR was defined as the percentage of participants who achieved a complete response (CR: disappearance of all target lesions) or partial response (PR: at least a 30% decrease in the sum of diameters \[SOD\] of target lesions) according to RECIST 1.1 by Investigator review. Because imaging was assessed prior to surgery, a confirmation assessment of CR or PR was not obtained. Participants with missing outcome for objective response were considered non-responders. The percentage of participants who experienced a CR or PR based on RECIST 1.1 following the first combination regimen is presented.

Participant flow

Pre-assignment details

Sixty participants were allocated and treated on study.

Participants by arm

Arm	Count
Cohort A: KNp / KAC Participants received pembrolizumab (K) 200 mg on Cycle 1 Day 1 followed by pembrolizumab 200 mg in Cycles 2-5 on Day 1 (once every 3 weeks; Q3W) PLUS nab-paclitaxel (KNp) starting at 125 mg/m\^2 in Cycles 2-5 on Days 1, 8 and 15 (once each week; QW). This was followed by pembrolizumab (K) 200 mg in Cycles 6-9 on Day 1 (Q3W) PLUS doxorubicin (A) 60 mg/m\^2 in Cycles 6-9 on Day 1 (Q3W) PLUS cyclophosphamide (C) 600 mg/m\^2 in Cycles 6-9 on Day 1 (Q3W). All treatments were administered via intravenous (IV) infusion except for doxorubicin (A), which was administered via IV injection. Each cycle was 21 days.	10
Cohort B: KNpCb (Regimen 1) / KAC Participants first received KNpCb Regimen 1 which consisted of: pembrolizumab (K) 200 mg on Cycle 1 Day 1 PLUS nab-paclitaxel (KNp) starting at 100 mg/m\^2 in Cycles 2-5 on Days 1, 8 and 15 (QW) PLUS carboplatin (Cb) starting at Area Under the Curve (AUC) 6 in Cycles 2-5 on Day 1 (Q3W). This was followed by pembrolizumab (K) 200 mg in Cycles 6-9 on Day 1 (Q3W) PLUS doxorubicin (A) 60 mg/m\^2 in Cycles 6-9 on Day 1 (Q3W) PLUS cyclophosphamide (C) 600 mg/m\^2 in Cycles 6-9 on Day 1 (Q3W). All treatments were administered via IV infusion except for doxorubicin (A), which was administered via IV injection. Each cycle was 21 days.	10
Cohort C: KNpCb (Regimen 2) / KAC Participants first received KNpCb Regimen 2 which consisted of: pembrolizumab (K) 200 mg on Cycle 1 Day 1 PLUS nab-paclitaxel (KNp) starting at 125 mg/m\^2 in Cycles 2-5 on Days 1, 8 and 15 (QW) PLUS carboplatin (Cb) starting at AUC 5 in Cycles 2-5 on Day 1 (Q3W). This was followed by pembrolizumab (K) 200 mg in Cycles 6-9 on Day 1 (Q3W) PLUS doxorubicin (A) 60 mg/m\^2 in Cycles 6-9 on Day 1 (Q3W) PLUS cyclophosphamide (C) 600 mg/m\^2 in Cycles 6-9 on Day 1 (Q3W). All treatments were administered via IV infusion except for doxorubicin (A), which was administered via IV injection. Each cycle was 21 days.	10
Cohort D: KNpCb (Regimen 3) / KAC Participants first received KNpCb Regimen 3 which consisted of: pembrolizumab (K) 200 mg on Cycle 1 Day 1 PLUS nab-paclitaxel (KNp) starting at 125 mg/m\^2 in Cycles 2-5 on Days 1, 8 and 15 (QW) PLUS carboplatin (Cb) starting at AUC 2 in Cycles 2-5 on Days 1, 8 and 15 (QW). This was followed by pembrolizumab (K) 200 mg in Cycles 6-9 on Day 1 PLUS doxorubicin (A) 60 mg/m\^2 in Cycles 6-9 on Day 1 (Q3W) PLUS cyclophosphamide (C) 600 mg/m\^2 in Cycles 6-9 on Day 1 (Q3W) in Cycles 6-9 on Day 1 (Q3W). All treatments were administered via IV infusion except for doxorubicin (A), which was administered via IV injection. Each cycle was 21 days.	10
Cohort E: KTCb (Regimen 1) / KAC Participants first received KTCb Regimen 1 which consisted of: pembrolizumab (K) 200 mg on Cycle 1 Day 1 PLUS paclitaxel (T) starting at 80mg/m\^2 in Cycles 2-5 on Days 1, 8, and 15 (QW) PLUS carboplatin (Cb) starting at AUC 5 in Cycles 2-5 on Day 1 (Q3W). This was followed by pembrolizumab (K) 200 mg in Cycles 6-9 on Day 1 (Q3W) PLUS doxorubicin (A) 60 mg/m\^2 in Cycles 6-9 on Day 1 (Q3W) PLUS cyclophosphamide (C) 600 mg/m\^2 in Cycles 6-9 on Day 1 (Q3W). All treatments were administered via IV infusion except for doxorubicin (A), which was administered via IV injection. Each cycle was 21 days.	10
Cohort F: KTCb (Regimen 2) / KAC Participants first received KTCb Regimen 2 which consisted of: pembrolizumab (K) 200 mg on Cycle 1 Day 1 PLUS paclitaxel (T) starting at 80mg/m\^2 in Cycles 2-5 on Days 1, 8, and 15 PLUS carboplatin (Cb) starting at AUC 2 in Cycles 2-5 on Days 1, 8 and 15 (QW). This was followed by pembrolizumab (K) 200 mg in Cycles 6-9 on Day 1 (Q3W) PLUS doxorubicin (A) 60 mg/m\^2 in Cycles 6-9 on Day 1 (Q3W) PLUS cyclophosphamide (C) 600 mg/m\^2 in Cycles 6-9 on Day 1 (Q3W). All treatments were administered via IV infusion except for doxorubicin (A), which was administered via IV injection. Each cycle was 21 days.	10
Total	60

Withdrawals & dropouts

Period	Reason	FG000	FG001	FG002	FG003	FG004	FG005
Overall Study	Death	4	0	0	1	1	0
Overall Study	Withdrawal by Subject	0	1	0	0	0	0

Baseline characteristics

Characteristic	Cohort A: KNp / KAC	Cohort B: KNpCb (Regimen 1) / KAC	Cohort C: KNpCb (Regimen 2) / KAC	Cohort D: KNpCb (Regimen 3) / KAC	Cohort E: KTCb (Regimen 1) / KAC	Cohort F: KTCb (Regimen 2) / KAC	Total
Age, Continuous	51.5 Years STANDARD_DEVIATION 11.1	49.5 Years STANDARD_DEVIATION 11.3	43.2 Years STANDARD_DEVIATION 6.4	42.3 Years STANDARD_DEVIATION 11.2	56.7 Years STANDARD_DEVIATION 11.9	52.1 Years STANDARD_DEVIATION 11.3	49.2 Years STANDARD_DEVIATION 11.4
Ethnicity (NIH/OMB) Hispanic or Latino	0 Participants	2 Participants	1 Participants	0 Participants	0 Participants	0 Participants	3 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	10 Participants	8 Participants	9 Participants	10 Participants	10 Participants	10 Participants	57 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Asian	5 Participants	2 Participants	5 Participants	7 Participants	1 Participants	1 Participants	21 Participants
Race (NIH/OMB) Black or African American	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) More than one race	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) White	5 Participants	8 Participants	5 Participants	3 Participants	9 Participants	9 Participants	39 Participants
Sex: Female, Male Female	10 Participants	10 Participants	10 Participants	10 Participants	10 Participants	10 Participants	60 Participants
Sex: Female, Male Male	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk	EG003 affected / at risk	EG004 affected / at risk	EG005 affected / at risk
deaths Total, all-cause mortality	4 / 10	0 / 10	0 / 10	1 / 10	1 / 10	0 / 10
other Total, other adverse events	10 / 10	10 / 10	10 / 10	10 / 10	10 / 10	10 / 10
serious Total, serious adverse events	5 / 10	4 / 10	8 / 10	7 / 10	3 / 10	4 / 10

Outcome results

Primary

Number of Participants Who Discontinued Study Treatment Due to an Adverse Event (AE)

An AE was defined as any untoward medical occurrence in a participant administered study treatment and which does not necessarily have to have a causal relationship with this treatment. The number of participants who discontinued study treatment due to an AE is presented.

Time frame: Up to approximately 28 months (through Interim database cut-off date of 31-May-2018)

Population: The safety population consisted of all participants who received ≥1 dose of study treatment.

Arm	Measure	Value (COUNT_OF_PARTICIPANTS)
Cohort A: KNp / KAC	Number of Participants Who Discontinued Study Treatment Due to an Adverse Event (AE)	1 Participants
Cohort B: KNpCb (Regimen 1) / KAC	Number of Participants Who Discontinued Study Treatment Due to an Adverse Event (AE)	2 Participants
Cohort C: KNpCb (Regimen 2) / KAC	Number of Participants Who Discontinued Study Treatment Due to an Adverse Event (AE)	1 Participants
Cohort D: KNpCb (Regimen 3) / KAC	Number of Participants Who Discontinued Study Treatment Due to an Adverse Event (AE)	5 Participants
Cohort E: KTCb (Regimen 1) / KAC	Number of Participants Who Discontinued Study Treatment Due to an Adverse Event (AE)	2 Participants
Cohort F: KTCb (Regimen 2) / KAC	Number of Participants Who Discontinued Study Treatment Due to an Adverse Event (AE)	5 Participants

Primary

Number of Participants Who Experienced an Adverse Event (AE)

An AE was defined as any untoward medical occurrence in a participant administered study treatment and which does not necessarily have to have a causal relationship with this treatment. The number of participants who experienced an AE either prior to or after definitive surgery is presented.

Time frame: Up to approximately 28 months (through Interim database cut-off date of 31-May-2018)

Population: The safety population consisted of all participants who received ≥1 dose of study treatment.

Arm	Measure	Value (COUNT_OF_PARTICIPANTS)
Cohort A: KNp / KAC	Number of Participants Who Experienced an Adverse Event (AE)	10 Participants
Cohort B: KNpCb (Regimen 1) / KAC	Number of Participants Who Experienced an Adverse Event (AE)	10 Participants
Cohort C: KNpCb (Regimen 2) / KAC	Number of Participants Who Experienced an Adverse Event (AE)	10 Participants
Cohort D: KNpCb (Regimen 3) / KAC	Number of Participants Who Experienced an Adverse Event (AE)	10 Participants
Cohort E: KTCb (Regimen 1) / KAC	Number of Participants Who Experienced an Adverse Event (AE)	10 Participants
Cohort F: KTCb (Regimen 2) / KAC	Number of Participants Who Experienced an Adverse Event (AE)	10 Participants

Primary

Number of Participants With Dose Limiting Toxicities (DLTs) Graded Using National Cancer Institute Common Toxicity Criteria for Adverse Events Version 4.0 (NCI CTCAE v4.0)

The following events, if considered to be study-treatment-related by the Investigator, were considered a DLT: * Hematologic: * Grade 4 neutropenia lasting ≥8 days; * Febrile neutropenia Grade 3 or Grade 4; or * Grade 4 thrombocytopenia requiring platelet transfusion, or Grade 3 thrombocytopenia with bleeding * Non-hematologic: * Grade 4 toxicity; * Grade ≥3 symptomatic hepatic toxicities lasting \>48 hours, or Grade ≥3 asymptomatic hepatic toxicities lasting ≥7 days; or * Grade ≥3 non-hematologic, non-hepatic organ toxicity, with exceptions * Other: * Any treatment delays for ≥14 days due to unresolved toxicity; * Grade 5 treatment-related adverse event (AE); * A dose reduction of study treatment during the DLT evaluation period.

Time frame: Cycle 1 Day 1 through end of Cycle 3 and Cycle 6 Day 1 through end of Cycle 7 (Up to ~150 days from first dose of first combination regimen); Each cycle was 21 days.

Population: The DLT evaluable population consisted of all participants who received ≥1 dose of study treatment.

Arm	Measure	Value (COUNT_OF_PARTICIPANTS)
Cohort A: KNp / KAC	Number of Participants With Dose Limiting Toxicities (DLTs) Graded Using National Cancer Institute Common Toxicity Criteria for Adverse Events Version 4.0 (NCI CTCAE v4.0)	2 Participants
Cohort B: KNpCb (Regimen 1) / KAC	Number of Participants With Dose Limiting Toxicities (DLTs) Graded Using National Cancer Institute Common Toxicity Criteria for Adverse Events Version 4.0 (NCI CTCAE v4.0)	4 Participants
Cohort C: KNpCb (Regimen 2) / KAC	Number of Participants With Dose Limiting Toxicities (DLTs) Graded Using National Cancer Institute Common Toxicity Criteria for Adverse Events Version 4.0 (NCI CTCAE v4.0)	6 Participants
Cohort D: KNpCb (Regimen 3) / KAC	Number of Participants With Dose Limiting Toxicities (DLTs) Graded Using National Cancer Institute Common Toxicity Criteria for Adverse Events Version 4.0 (NCI CTCAE v4.0)	6 Participants
Cohort E: KTCb (Regimen 1) / KAC	Number of Participants With Dose Limiting Toxicities (DLTs) Graded Using National Cancer Institute Common Toxicity Criteria for Adverse Events Version 4.0 (NCI CTCAE v4.0)	0 Participants
Cohort F: KTCb (Regimen 2) / KAC	Number of Participants With Dose Limiting Toxicities (DLTs) Graded Using National Cancer Institute Common Toxicity Criteria for Adverse Events Version 4.0 (NCI CTCAE v4.0)	4 Participants

Secondary

Event-Free Survival (EFS) Rate at Month 12

EFS was defined as the time from the first dose date of study treatment to any of the following events: progression of disease that precludes definitive surgery, disease recurrence (for participants with complete surgical resection), progression (for participants with incomplete surgical resection), or death due to any cause. Participants without documented events were censored at the date of the last disease status assessment. The Kaplan-Meier estimates of the percentage of participants who were event free at Month 12 are presented (through Final Analysis cut-off of 18-Nov-2019).

Time frame: Month 12