First-in-Human Study of the Safety, Tolerability, and Pharmacokinetic/Pharmacodynamic Profile of VX-984 in Combination With Chemotherapy

• Sponsor: EMD Serono Research & Development Institute, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02644278
• Collaborator: Merck KGaA, Darmstadt, Germany (Industry)
• Enrollment: 15
• Locations: 5
• Arms: 4
• Actual Duration (Months): 19.6
• Patients Per Site: 3
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

The purpose of this study was to evaluate the safety and tolerability of VX-984 (M9831) administered alone and in combination with pegylated liposomal doxorubicin (PLD), and to determine the maximum tolerated dose (MTD) and preliminary evidence of efficacy of VX-984 in combination with PLD in participants with advanced solid tumors.

Condition or Disease	Intervention/Treatment	Phase
Advanced Solid Tumor	Drug: VX-984 120 mg + PLD 40 mg/m^2; Drug: VX-984 240 mg + PLD 40 mg/m^2; Drug: VX-984 480 mg + PLD 40 mg/m^2; Drug: VX-984 720 mg + PLD 40 mg/m^2	Phase 1

Study Design

• Study Type: Interventional
• Actual Enrollment: 15 participants
• Intervention Model: Sequential Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: An Open-Label, Phase 1, First-in-Human Study of the Safety, Tolerability, and Pharmacokinetic/Pharmacodynamic Profile of VX-984 in Combination With Chemotherapy in Subjects With Advanced Solid Tumors
• Actual Study Start Date: Feb 29, 2016
• Actual Primary Completion Date: Oct 19, 2017
• Actual Study Completion Date: Oct 19, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: VX-984 120 mg + PLD 40 mg/m^2	Drug: VX-984 120 mg + PLD 40 mg/m^2; Participants received VX-984 orally 120 milligram (mg) orally once daily alone on Days -14 to -12 of a 14-day Lead-in Period, followed by VX-984 120 mg in combination with pegylated liposomal doxorubicin (PLD) 40 milligram per square meter (mg/m^2) administered intravenous infusion, with PLD administered on Day 1 and VX-984 administered on Day 2 to Day 4 for up to six 28-day cycle or until disease progression unacceptable toxicities, withdrawal of consent, or until exposure to PLD exceeded 550 mg/m^2.; Other Names: M9831
Experimental: VX-984 240 mg + PLD 40 mg/m^2	Drug: VX-984 240 mg + PLD 40 mg/m^2; Participants received VX-984 orally 240 mg orally once daily alone on Days -14 to -12 of a 14-day Lead-in Period, followed by VX-984 240 mg in combination with PLD 40 mg/m^2 administered intravenous infusion, with PLD administered on Day 1 and VX-984 administered on Day 2 to Day 4 for up to six 28-day cycle or until disease progression unacceptable toxicities, withdrawal of consent, or until exposure to PLD exceeded 550 mg/m^2.
Experimental: VX-984 480 mg + PLD 40 mg/m^2	Drug: VX-984 480 mg + PLD 40 mg/m^2; Participants received VX-984 orally 480 mg orally once daily alone on Days -14 to -12 of a 14-day Lead-in Period, followed by VX-984 480 mg in combination with PLD 40 mg/m^2 administered intravenous infusion, with PLD administered on Day 1 and VX-984 administered on Day 2 to Day 4 for up to six 28-day cycle or until disease progression unacceptable toxicities, withdrawal of consent, or until exposure to PLD exceeded 550 mg/m^2.
Experimental: VX-984 720 mg + PLD 40 mg/m^2	Drug: VX-984 720 mg + PLD 40 mg/m^2; Participants received VX-984 orally 720 mg orally once daily alone on Days -14 to -12 of a 14-day Lead-in Period, followed by VX-984 720 mg in combination with PLD 40 mg/m^2 administered intravenous infusion, with PLD administered on Day 1 and VX-984 administered on Day 2 to Day 4 for up to six 28-day cycle or until disease progression unacceptable toxicities, withdrawal of consent, or until exposure to PLD exceeded 550 mg/m^2.

Outcome Measures

Primary Outcome Measures

1. Part A: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious TEAEs [Baseline up to 28 days after the last dose of study treatment, assessed up to 53.1 weeks]

   An adverse event (AE) was defined as any unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of study drug, whether or not considered related to the study drug. A serious AE was an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. Treatment-Emergent adverse events (TEAEs) were defined as AEs that were reported or worsened on or after the start of study drug dosing through the 28-day Safety Follow-up visit. TEAEs included both Serious TEAEs and non-serious TEAEs.

2. Part A: Number of Participants Who Experienced Dose Limiting Toxicity (DLT) [Cycle 1 (each cycle is 28 days)]

   DLT was defined using National cancer Institute Common Toxicity Criteria for Adverse Events Version 4.0 as any of the following toxicities: Grade 4 neutropenia for more than 7 days; Grade greater than or equal to (>=) 3 febrile neutropenia; Grade 4 or Grade 3 thrombocytopenia with bleeding. Grade >= 3 uncontrolled nausea/vomiting and/or diarrhea despite adequate and optimal treatment and Grade >= 3 any non- hematological adverse event (AE), except the aforementioned gastrointestinal events and alopecia.

3. Part A: Number of Participants With Toxicity Grade 3 or Higher in Laboratory Abnormalities [Baseline up to 28 days after the last dose of study treatment, assessed up to 53.1 weeks]

   The laboratory measurements included hematology and serum chemistry. It had been graded according to National Cancer Institute - Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4.03 into Grade 1 (mild), Grade 2 (moderate), Grade 3 (severe), Grade 4 (Life-threatening) and Grade 5 = death. Participants with grade 3 or higher were reported.

4. Part A: Maximum Tolerated Dose (MTD) of VX-984 in Combination With Pegylated Liposomal Doxorubicin (PLD) [Up to Cycle 1 Day 28 (each cycle is 28 days)]

   The MTD was defined as the combination dose associated with the highest probability that Dose limiting toxicity (DLT) events will occur in 16.6 percent to less than 33.3 percent participants as the combination dose that not exceeded the overdose criterion (more than 25 percent probability that DLT events occurred less than or equal to (>=) 33 percent of participants. DLT was defined using National Cancer Institute Common Toxicity Criteria for Adverse Events Version 4.0.

5. Part A: Number of Participants With Clinical Significant Abnormalities in Vital Signs [Baseline up to 28 days after the last dose of study treatment, assessed up to 53.1 weeks]

   Vital signs assessment included blood pressure, pulse rate and body temperature. Clinical significance was determined by the investigator. Number of participants with clinical significant abnormalities in vital Signs reported here.

6. Part A: Number of Participants With Clinical Significant Abnormalities Echocardiograms [Baseline up to 28 days after the last dose of study treatment, assessed up to 53.1 weeks]

   Echocardiogram is a graphic outline of the heart's movement. Clinical significance was determined by the investigator. Number of participants with clinical significant abnormalities in Echocardiograms reported here.

7. Part A: Number of Participants With Clinical Significant Abnormalities in Electrocardiogram(ECG) Parameters [Baseline up to 28 days after the last dose of study treatment, assessed up to 53.1 weeks]

   ECG parameters included heart rate, pulse rate, QRS,QT, RR, QTcB and QTcF. Clinical significance was determined by the investigator. Number of participants with clinical significant abnormalities in ECG parameters reported here.

Secondary Outcome Measures

1. Part A: Area Under Plasma Concentration (AUC) During a Dosing Interval of VX-984 [Pre-dose and at 0.5, 1, 2, 4, 8, and 24 hours post-dose on Day -12 and Day 4 in Cycle 1; Pre-dose and at 0.5, 1, 2, 4 hours post-dose on Day 2 in Cycle 1 (each Cycle is of 28 days)]

   AUC is the area under the plasma concentration curve within 1 dosing interval.

2. Part A: Maximum Observed Plasma Concentration (Cmax) of VX-984 [Pre-dose and at 0.5, 1, 2, 4, 8, and 24 hours post-dose on Day -12 and Day 4 in Cycle 1; Pre-dose and at 0.5, 1, 2, 4 hours post-dose on Day 2 in Cycle 1 (each Cycle is of 28 days)]

   Pharmacokinetic PK parameter Cmax was obtained directly from the concentration versus time curve.

3. Part A: Time to Reach Maximum Plasma Concentration (Tmax) of VX-984 [Pre-dose and at 0.5, 1, 2, 4, 8, and 24 hours post-dose on Day -12 and Day 4 in Cycle 1; Pre-dose and at 0.5, 1, 2, 4 hours post-dose on Day 2 in Cycle 1 (each Cycle is of 28 days)]

   Time to reach the maximum plasma concentration (Tmax) was obtained directly from the concentration versus time curve.

4. Part A: Minimum Observed Plasma Concentration During Dosing Interval (Cmin) of VX-984 [Pre-dose and at 0.5, 1, 2, 4, 8, and 24 hours post-dose on Day -12 and Day 4 in Cycle 1; Pre-dose and at 0.5, 1, 2, 4 hours post-dose on Day 2 in Cycle 1 (each Cycle is of 28 days)]

   Cmin is minimum observed plasma concentration obtained directly from the concentration versus time curve.

5. Part A: Area Under the Plasma Concentration Curve From Time Zero to 96 Hours Post Dose AUC(0-96h) of Pegylated Liposomal Doxorubicin [Pre-infusion and at 1, 2, 4, 6, 24, 72 and 96 hours after infusion in Cycle 1 (each Cycle is of 28 days)]

   The AUC(0-96h) was estimated by determining the total area under the curve of the concentration versus curve extrapolated from 0 to 96 hours.

6. Part A: Maximum Observed Plasma Concentration (Cmax0-96h) From Time Zero to 96 Hours Post Dose of Pegylated Liposomal Doxorubicin [Pre-infusion and at 1, 2, 4, 6, 24, 72 and 96 hours after infusion in Cycle 1 (each Cycle is of 28 days)]

   Cmax is the maximum observed plasma concentration obtained directly from concentration versus time curve from zero to 96 hours

7. Part A: Time to Reach Maximum Plasma Concentration From Zero to 96 Hours Post Dose (tmax0-96h) of Pegylated Liposomal Doxorubicin [Pre-infusion and at 1, 2, 4, 6, 24, 72 and 96 hours after infusion in Cycle 1 (each Cycle is of 28 days)]

   Tmax is time to reach maximum observed plasma concentration obtained directly from the concentration versus time curve from zero to 96 hours post dose.

8. Part A: Number of Participants With Best Overall Response Evaluated by Response Criteria Evaluation (RECIST 1.1) [Up to 2 years]

   The best overall response was defined as the number of participants who had achieved complete response (CR) or partial response (PR) as the best overall response according to radiological assessments as adjudicated by the IRC from randomization until the first occurrence of progressive disease (PD). CR: Complete Response (CR) defined as disappearance of all target and non-target lesions and any pathological lymph nodes (whether target or non-target) must have reduction in short axis to < 10 mm. Partial response (PR) defined as at least a 30% decrease in the sum of diameters of target lesions taking as reference the baseline sum diameters. PD defined as an increase of at least 20% in the sum of the diameters of target lesions, taking as reference the smallest sum of the diameters of target lesions recorded since treatment started.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Participants (male and female for Part A and female for Part B) were at least 18 year of age.

• Part A Participants with histologically or cytologically confirmed malignant advanced solid tumors, who had progressed on at least 1 prior chemotherapy, and for whom either

1. No standard care available

2. PLD at the dose and schedule being used might be considered standard of care

• Part B

1. Participants with histologically confirmed advanced primary endometrial cancer (locally advanced and incurable endometrial cancer that had been treated with surgery and/or radiation or is ineligible for such treatment), or recurrent or metastatic endometrial cancer, and

2. Completed 1 line of chemotherapy treatment with a platinum-containing regimen in the advanced setting

• Measurable disease according to RECIST criteria (Version 1.1)

• Life expectancy of at least 12 weeks

• Hematological and biochemical indices within acceptable ranges shown at screening.

• Normal left ventricular ejection fraction on screening assessed by transthoracic echocardiogram or multiple gated acquisition (MUGA) scan

Exclusion Criteria:

• Previous radiotherapy (unless brachytherapy), endocrine therapy, chemotherapy, or exposure to investigational medicinal products during the 4 weeks (6 weeks for nitrosoureas and Mitomycin-C) or 4 drug half-lives before the planned administration of the first dose of study drug, whichever is greater. Previous immunotherapy during the 4 weeks before the planned administration of the first dose of study drug.

• For Part B only:

1. Participants with uterine carcinosarcoma

2. Prior anthracycline therapy

3. More than 1 prior chemotherapy regimen (a participant was received first- line carboplatin and taxane and then received the same taxane second- line were considered to have had 1 prior chemotherapy regimen)

• Unresolved toxicity of Common Terminology Criteria for Adverse Events (CTCAE) Grade 2 or greater from previous anti-cancer therapy or radiotherapy

• History of spinal cord compression or brain metastases, unless asymptomatic, treated, stable, and not requiring treatment with steroids for at least 4 weeks before the planned administration of the first dose of study drug. Any history of leptomeningeal metastases.

• Female participants who was pregnant or lactating at Screening, or planned to become pregnant while on study or within 6 months after the last dose of study drug

• Female participants of childbearing potential were adhere to contraception guidelines as outlined in the protocol. Female participants were considered to be of nonchildbearing potential if they had undergone surgical hysterectomy or bilateral oophorectomy or had been amenorrheic for more than 2 years with a screening serum follicle-stimulating hormone (FSH) level within the laboratory's reference range for postmenopausal females

• Male participants with pregnant or lactating partners or partners who planned to become pregnant while on study or within 6 months after the planned administration of the last dose of study drug

• Major surgery ≤4 weeks before first dose of study drug, or incomplete recovery from a prior major surgical procedure

• Cardiac conditions

• Prior bone marrow transplant

• Extensive radiotherapy (to greater than 15% of bone marrow)

• Any other condition that in the investigator's opinion would not make the participant a good candidate for the clinical study,

• Part B: Current active malignancies of other types, with the exception of adequately treated cone-biopsied in situ carcinoma of the cervix uteri and basal or squamous cell carcinoma of the skin. Prior cancer in remission for 2 years or more would not be excluded.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Scottsdale	Arizona	United States	85258
2		Boston	Massachusetts	United States	02215
3		Nashville	Tennessee	United States	37203
4		Dallas	Texas	United States	75246
5		Houston	Texas	United States	77030

Sponsors and Collaborators

• EMD Serono Research & Development Institute, Inc.
• Merck KGaA, Darmstadt, Germany

Investigators

• Study Director: Medical Responsible, EMD Serono Research & Development Institute, Inc., a subsidiary of Merck KGaA, Darmstadt, Germany

Study Documents (Full-Text)

• Study Protocol - Aug 21, 2017
• Statistical Analysis Plan - Jan 26, 2018

More Information

Publications

None provided.

• Responsible Party: EMD Serono Research & Development Institute, Inc.
• ClinicalTrials.gov Identifier: NCT02644278
• Other Study ID Numbers: MS201926-0001; VX15-984-001
• First Posted: Dec 31, 2015
• Last Update Posted: Sep 9, 2019
• Last Verified: Jul 1, 2019

• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by EMD Serono Research & Development Institute, Inc.: VX15-984-001; VX-984; M9831; Advanced Solid Tumor; Pegylated liposomal doxorubicin

Study Results

Participant Flow

Pre-assignment Detail	First Participant First Visit: 29 Feb 2016-Last Participant Last Visit: 19-Oct-2017; A total of 15 participants were enrolled in Part A and no participants were enrolled for Part B as the study was discontinued during dose escalation in Part A, based on business related reasons as decided by the Sponsor.

Arm/Group Title	VX-984 120 mg + PLD 40 mg/m^2	VX-984 240 mg + PLD 40 mg/m^2	VX-984 480 mg + PLD 40 mg/m^2	VX-984 720 mg + PLD 40 mg/m^2
Arm/Group Description	Participants received VX-984 orally 120 milligram (mg) once daily alone on Days -14 to -12 of a 14-day Lead-in Period, followed by VX-984 120 mg in combination with pegylated liposomal doxorubicin (PLD) 40 milligram per square meter (mg/m^2) administered intravenous infusion, with PLD administered on Day 1 and VX-984 administered on Day 2 to Day 4 for up to six 28-day cycle or until disease progression unacceptable toxicities withdrawal of consent, or until exposure to PLD exceeded 550 mg/m^2.	Participants received VX-984 orally 240 mg orally once daily alone on Days -14 to -12 of a 14-day Lead-in Period, followed by VX-984 240 mg in combination with PLD 40 mg/m^2 administered intravenous infusion, with PLD administered on Day 1 and VX-984 administered on Day 2 to Day 4 for up to six 28-day cycle or until disease progression unacceptable toxicities, withdrawal of consent, or until exposure to PLD exceeded 550 mg/m^2.	Participants received VX-984 orally 480 mg orally once daily alone on Days -14 to -12 of a 14-day Lead-in Period, followed by VX-984 480 mg in combination with PLD 40 mg/m^2 administered intravenous infusion, with PLD administered on Day 1 and VX-984 administered on Day 2 to Day 4 for up to six 28-day cycle or until disease progression unacceptable toxicities, withdrawal of consent, or until exposure to PLD exceeded 550 mg/m^2.	Participants received VX-984 orally 720 mg orally once daily alone on Days -14 to -12 of a 14-day Lead-in Period, followed by VX-984 720 mg in combination with PLD 40 mg/m^2 administered intravenous infusion, with PLD administered on Day 1 and VX-984 administered on Day 2 to Day 4 for up to six 28-day cycle or until disease progression unacceptable toxicities, withdrawal of consent, or until exposure to PLD exceeded 550 mg/m^2.
Period Title: Overall Study
STARTED	3	3	6	3
COMPLETED	3	3	6	3
NOT COMPLETED	0	0	0	0

Baseline Characteristics

Arm/Group Title	VX-984 120 mg + PLD 40 mg/m^2	VX-984 240 mg + PLD 40 mg/m^2	VX-984 480 mg + PLD 40 mg/m^2	VX-984 720 mg + PLD 40 mg/m^2	Total
Arm/Group Description	Participants received VX-984 orally 120 milligram (mg) once daily alone on Days -14 to -12 of a 14-day Lead-in Period, followed by VX-984 120 mg in combination with pegylated liposomal doxorubicin (PLD) 40 milligram per square meter (mg/m^2) administered intravenous infusion, with PLD administered on Day 1 and VX-984 administered on Day 2 to Day 4 for up to six 28-day cycle or until disease progression unacceptable toxicities withdrawal of consent, or until exposure to PLD exceeded 550 mg/m^2.	Participants received VX-984 orally 240 mg orally once daily alone on Days -14 to -12 of a 14-day Lead-in Period, followed by VX-984 240 mg in combination with PLD 40 mg/m^2 administered intravenous infusion, with PLD administered on Day 1 and VX-984 administered on Day 2 to Day 4 for up to six 28-day cycle or until disease progression unacceptable toxicities, withdrawal of consent, or until exposure to PLD exceeded 550 mg/m^2.	Participants received VX-984 orally 480 mg orally once daily alone on Days -14 to -12 of a 14-day Lead-in Period, followed by VX-984 480 mg in combination with PLD 40 mg/m^2 administered intravenous infusion, with PLD administered on Day 1 and VX-984 administered on Day 2 to Day 4 for up to six 28-day cycle or until disease progression unacceptable toxicities, withdrawal of consent, or until exposure to PLD exceeded 550 mg/m^2.	Participants received VX-984 orally 720 mg orally once daily alone on Days -14 to -12 of a 14-day Lead-in Period, followed by VX-984 720 mg in combination with PLD 40 mg/m^2 administered intravenous infusion, with PLD administered on Day 1 and VX-984 administered on Day 2 to Day 4 for up to six 28-day cycle or until disease progression unacceptable toxicities, withdrawal of consent, or until exposure to PLD exceeded 550 mg/m^2.	Total of all reporting groups
Overall Participants	3	3	6	3	15
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	51.0 (17.32)	68.7 (5.77)	57.5 (9.09)	64.3 (8.33)	59.8 (11.28)
Sex: Female, Male (Count of Participants)
Female	3 100%	3 100%	5 83.3%	3 100%	14 93.3%
Male	0 0%	0 0%	1 16.7%	0 0%	1 6.7%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%	0 0%	0 0%	0 0%	0 0%
Not Hispanic or Latino	3 100%	3 100%	6 100%	3 100%	15 100%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%	0 0%
Asian	0 0%	1 33.3%	1 16.7%	0 0%	2 13.3%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%	0 0%
Black or African American	1 33.3%	0 0%	0 0%	0 0%	1 6.7%
White	2 66.7%	2 66.7%	5 83.3%	3 100%	12 80%
More than one race	0 0%	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%	0 0%

Outcome Measures

1. Primary Outcome

Title	Part A: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious TEAEs
Description	An adverse event (AE) was defined as any unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of study drug, whether or not considered related to the study drug. A serious AE was an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. Treatment-Emergent adverse events (TEAEs) were defined as AEs that were reported or worsened on or after the start of study drug dosing through the 28-day Safety Follow-up visit. TEAEs included both Serious TEAEs and non-serious TEAEs.
Time Frame	Baseline up to 28 days after the last dose of study treatment, assessed up to 53.1 weeks

Outcome Measure Data

Analysis Population Description

The safety analysis set included all participants who had received at least 1 dose of the study treatment.

Arm/Group Title	VX-984 120 mg + PLD 40 mg/m^2	VX-984 240 mg + PLD 40 mg/m^2	VX-984 480 mg + PLD 40 mg/m^2	VX-984 720 mg + PLD 40 mg/m^2
Arm/Group Description	Participants received VX-984 orally 120 milligram (mg) once daily alone on Days -14 to -12 of a 14-day Lead-in Period, followed by VX-984 120 mg in combination with pegylated liposomal doxorubicin (PLD) 40 milligram per square meter (mg/m^2) administered intravenous infusion, with PLD administered on Day 1 and VX-984 administered on Day 2 to Day 4 for up to six 28-day cycle or until disease progression unacceptable toxicities withdrawal of consent, or until exposure to PLD exceeded 550 mg/m^2.	Participants received VX-984 orally 240 mg orally once daily alone on Days -14 to -12 of a 14-day Lead-in Period, followed by VX-984 240 mg in combination with PLD 40 mg/m^2 administered intravenous infusion, with PLD administered on Day 1 and VX-984 administered on Day 2 to Day 4 for up to six 28-day cycle or until disease progression unacceptable toxicities, withdrawal of consent, or until exposure to PLD exceeded 550 mg/m^2.	Participants received VX-984 orally 480 mg orally once daily alone on Days -14 to -12 of a 14-day Lead-in Period, followed by VX-984 480 mg in combination with PLD 40 mg/m^2 administered intravenous infusion, with PLD administered on Day 1 and VX-984 administered on Day 2 to Day 4 for up to six 28-day cycle or until disease progression unacceptable toxicities, withdrawal of consent, or until exposure to PLD exceeded 550 mg/m^2.	Participants received VX-984 orally 720 mg orally once daily alone on Days -14 to -12 of a 14-day Lead-in Period, followed by VX-984 720 mg in combination with PLD 40 mg/m^2 administered intravenous infusion, with PLD administered on Day 1 and VX-984 administered on Day 2 to Day 4 for up to six 28-day cycle or until disease progression unacceptable toxicities, withdrawal of consent, or until exposure to PLD exceeded 550 mg/m^2.
Measure Participants	3	3	6	3
Any TEAE	3 100%	3 100%	6 100%	3 100%
Any Serious TEAE	2 66.7%	0 0%	3 50%	1 33.3%

2. Primary Outcome

Title	Part A: Number of Participants Who Experienced Dose Limiting Toxicity (DLT)
Description	DLT was defined using National cancer Institute Common Toxicity Criteria for Adverse Events Version 4.0 as any of the following toxicities: Grade 4 neutropenia for more than 7 days; Grade greater than or equal to (>=) 3 febrile neutropenia; Grade 4 or Grade 3 thrombocytopenia with bleeding. Grade >= 3 uncontrolled nausea/vomiting and/or diarrhea despite adequate and optimal treatment and Grade >= 3 any non- hematological adverse event (AE), except the aforementioned gastrointestinal events and alopecia.
Time Frame	Cycle 1 (each cycle is 28 days)

Outcome Measure Data

Analysis Population Description

DLT evaluable set included all participants in the safety analysis set who either met the minimum exposure criterion and had sufficient safety evaluations (as determined by the Investigators and the Sponsor) or have had a DLT.

Arm/Group Title	VX-984 120 mg + PLD 40 mg/m^2	VX-984 240 mg + PLD 40 mg/m^2	VX-984 480 mg + PLD 40 mg/m^2	VX-984 720 mg + PLD 40 mg/m^2
Arm/Group Description	Participants received VX-984 orally 120 milligram (mg) once daily alone on Days -14 to -12 of a 14-day Lead-in Period, followed by VX-984 120 mg in combination with pegylated liposomal doxorubicin (PLD) 40 milligram per square meter (mg/m^2) administered intravenous infusion, with PLD administered on Day 1 and VX-984 administered on Day 2 to Day 4 for up to six 28-day cycle or until disease progression unacceptable toxicities withdrawal of consent, or until exposure to PLD exceeded 550 mg/m^2.	Participants received VX-984 orally 240 mg orally once daily alone on Days -14 to -12 of a 14-day Lead-in Period, followed by VX-984 240 mg in combination with PLD 40 mg/m^2 administered intravenous infusion, with PLD administered on Day 1 and VX-984 administered on Day 2 to Day 4 for up to six 28-day cycle or until disease progression unacceptable toxicities, withdrawal of consent, or until exposure to PLD exceeded 550 mg/m^2.	Participants received VX-984 orally 480 mg orally once daily alone on Days -14 to -12 of a 14-day Lead-in Period, followed by VX-984 480 mg in combination with PLD 40 mg/m^2 administered intravenous infusion, with PLD administered on Day 1 and VX-984 administered on Day 2 to Day 4 for up to six 28-day cycle or until disease progression unacceptable toxicities, withdrawal of consent, or until exposure to PLD exceeded 550 mg/m^2.	Participants received VX-984 orally 720 mg orally once daily alone on Days -14 to -12 of a 14-day Lead-in Period, followed by VX-984 720 mg in combination with PLD 40 mg/m^2 administered intravenous infusion, with PLD administered on Day 1 and VX-984 administered on Day 2 to Day 4 for up to six 28-day cycle or until disease progression unacceptable toxicities, withdrawal of consent, or until exposure to PLD exceeded 550 mg/m^2.
Measure Participants	3	3	5	3
Count of Participants [Participants]	0 0%	0 0%	0 0%	0 0%

3. Primary Outcome

Title	Part A: Number of Participants With Toxicity Grade 3 or Higher in Laboratory Abnormalities
Description	The laboratory measurements included hematology and serum chemistry. It had been graded according to National Cancer Institute - Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4.03 into Grade 1 (mild), Grade 2 (moderate), Grade 3 (severe), Grade 4 (Life-threatening) and Grade 5 = death. Participants with grade 3 or higher were reported.
Time Frame	Baseline up to 28 days after the last dose of study treatment, assessed up to 53.1 weeks

Outcome Measure Data

Analysis Population Description

The safety analysis set included all participants who had received at least 1 dose of the study treatment.

Arm/Group Title	VX-984 120 mg + PLD 40 mg/m^2	VX-984 240 mg + PLD 40 mg/m^2	VX-984 480 mg + PLD 40 mg/m^2	VX-984 720 mg + PLD 40 mg/m^2
Arm/Group Description	Participants received VX-984 orally 120 milligram (mg) once daily alone on Days -14 to -12 of a 14-day Lead-in Period, followed by VX-984 120 mg in combination with pegylated liposomal doxorubicin (PLD) 40 milligram per square meter (mg/m^2) administered intravenous infusion, with PLD administered on Day 1 and VX-984 administered on Day 2 to Day 4 for up to six 28-day cycle or until disease progression unacceptable toxicities withdrawal of consent, or until exposure to PLD exceeded 550 mg/m^2.	Participants received VX-984 orally 240 mg orally once daily alone on Days -14 to -12 of a 14-day Lead-in Period, followed by VX-984 240 mg in combination with PLD 40 mg/m^2 administered intravenous infusion, with PLD administered on Day 1 and VX-984 administered on Day 2 to Day 4 for up to six 28-day cycle or until disease progression unacceptable toxicities, withdrawal of consent, or until exposure to PLD exceeded 550 mg/m^2.	Participants received VX-984 orally 480 mg orally once daily alone on Days -14 to -12 of a 14-day Lead-in Period, followed by VX-984 480 mg in combination with PLD 40 mg/m^2 administered intravenous infusion, with PLD administered on Day 1 and VX-984 administered on Day 2 to Day 4 for up to six 28-day cycle or until disease progression unacceptable toxicities, withdrawal of consent, or until exposure to PLD exceeded 550 mg/m^2.	Participants received VX-984 orally 720 mg orally once daily alone on Days -14 to -12 of a 14-day Lead-in Period, followed by VX-984 720 mg in combination with PLD 40 mg/m^2 administered intravenous infusion, with PLD administered on Day 1 and VX-984 administered on Day 2 to Day 4 for up to six 28-day cycle or until disease progression unacceptable toxicities, withdrawal of consent, or until exposure to PLD exceeded 550 mg/m^2.
Measure Participants	3	3	6	3
Participants With Hematology Abnormalities	1 33.3%	0 0%	5 83.3%	2 66.7%
Participants With Serum Chemistry Abnormalities	1 33.3%	1 33.3%	2 33.3%	1 33.3%

4. Primary Outcome

Title	Part A: Maximum Tolerated Dose (MTD) of VX-984 in Combination With Pegylated Liposomal Doxorubicin (PLD)
Description	The MTD was defined as the combination dose associated with the highest probability that Dose limiting toxicity (DLT) events will occur in 16.6 percent to less than 33.3 percent participants as the combination dose that not exceeded the overdose criterion (more than 25 percent probability that DLT events occurred less than or equal to (>=) 33 percent of participants. DLT was defined using National Cancer Institute Common Toxicity Criteria for Adverse Events Version 4.0.
Time Frame	Up to Cycle 1 Day 28 (each cycle is 28 days)

Outcome Measure Data

Analysis Population Description

DLT evaluable set included all participants in the safety analysis set who either met the minimum exposure criterion and had sufficient safety evaluations (as determined by the Investigators and the Sponsor) or have had a DLT.

Arm/Group Title	VX-984 120 mg + PLD 40 mg/m^2	VX-984 240 mg + PLD 40 mg/m^2	VX-984 480 mg + PLD 40 mg/m^2	VX-984 720 mg + PLD 40 mg/m^2
Arm/Group Description	Participants received VX-984 orally 120 milligram (mg) once daily alone on Days -14 to -12 of a 14-day Lead-in Period, followed by VX-984 120 mg in combination with pegylated liposomal doxorubicin (PLD) 40 milligram per square meter (mg/m^2) administered intravenous infusion, with PLD administered on Day 1 and VX-984 administered on Day 2 to Day 4 for up to six 28-day cycle or until disease progression unacceptable toxicities withdrawal of consent, or until exposure to PLD exceeded 550 mg/m^2.	Participants received VX-984 orally 240 mg orally once daily alone on Days -14 to -12 of a 14-day Lead-in Period, followed by VX-984 240 mg in combination with PLD 40 mg/m^2 administered intravenous infusion, with PLD administered on Day 1 and VX-984 administered on Day 2 to Day 4 for up to six 28-day cycle or until disease progression unacceptable toxicities, withdrawal of consent, or until exposure to PLD exceeded 550 mg/m^2.	Participants received VX-984 orally 480 mg orally once daily alone on Days -14 to -12 of a 14-day Lead-in Period, followed by VX-984 480 mg in combination with PLD 40 mg/m^2 administered intravenous infusion, with PLD administered on Day 1 and VX-984 administered on Day 2 to Day 4 for up to six 28-day cycle or until disease progression unacceptable toxicities, withdrawal of consent, or until exposure to PLD exceeded 550 mg/m^2.	Participants received VX-984 orally 720 mg orally once daily alone on Days -14 to -12 of a 14-day Lead-in Period, followed by VX-984 720 mg in combination with PLD 40 mg/m^2 administered intravenous infusion, with PLD administered on Day 1 and VX-984 administered on Day 2 to Day 4 for up to six 28-day cycle or until disease progression unacceptable toxicities, withdrawal of consent, or until exposure to PLD exceeded 550 mg/m^2.
Measure Participants	3	3	5	3
Number [milligram]	NA	NA	NA	NA

5. Secondary Outcome

Title	Part A: Area Under Plasma Concentration (AUC) During a Dosing Interval of VX-984
Description	AUC is the area under the plasma concentration curve within 1 dosing interval.
Time Frame	Pre-dose and at 0.5, 1, 2, 4, 8, and 24 hours post-dose on Day -12 and Day 4 in Cycle 1; Pre-dose and at 0.5, 1, 2, 4 hours post-dose on Day 2 in Cycle 1 (each Cycle is of 28 days)

Outcome Measure Data

Analysis Population Description

The Pharmacokinetic (PK) analysis included all participants who had received at least 1 dose of VX-984 or PLD and provided at least 1 measurable post dose concentration of VX-984 or one measurable post dose concentration of PLD.

Arm/Group Title	VX-984 120 mg + PLD 40 mg/m^2	VX-984 240 mg + PLD 40 mg/m^2	VX-984 480 mg + PLD 40 mg/m^2	VX-984 720 mg + PLD 40 mg/m^2
Arm/Group Description	Participants received VX-984 orally 120 milligram (mg) once daily alone on Days -14 to -12 of a 14-day Lead-in Period, followed by VX-984 120 mg in combination with pegylated liposomal doxorubicin (PLD) 40 milligram per square meter (mg/m^2) administered intravenous infusion, with PLD administered on Day 1 and VX-984 administered on Day 2 to Day 4 for up to six 28-day cycle or until disease progression unacceptable toxicities withdrawal of consent, or until exposure to PLD exceeded 550 mg/m^2.	Participants received VX-984 orally 240 mg orally once daily alone on Days -14 to -12 of a 14-day Lead-in Period, followed by VX-984 240 mg in combination with PLD 40 mg/m^2 administered intravenous infusion, with PLD administered on Day 1 and VX-984 administered on Day 2 to Day 4 for up to six 28-day cycle or until disease progression unacceptable toxicities, withdrawal of consent, or until exposure to PLD exceeded 550 mg/m^2.	Participants received VX-984 orally 480 mg orally once daily alone on Days -14 to -12 of a 14-day Lead-in Period, followed by VX-984 480 mg in combination with PLD 40 mg/m^2 administered intravenous infusion, with PLD administered on Day 1 and VX-984 administered on Day 2 to Day 4 for up to six 28-day cycle or until disease progression unacceptable toxicities, withdrawal of consent, or until exposure to PLD exceeded 550 mg/m^2.	Participants received VX-984 orally 720 mg orally once daily alone on Days -14 to -12 of a 14-day Lead-in Period, followed by VX-984 720 mg in combination with PLD 40 mg/m^2 administered intravenous infusion, with PLD administered on Day 1 and VX-984 administered on Day 2 to Day 4 for up to six 28-day cycle or until disease progression unacceptable toxicities, withdrawal of consent, or until exposure to PLD exceeded 550 mg/m^2.
Measure Participants	3	3	6	3
Geometric Mean (Geometric Coefficient of Variation) [nanogram hour per milliliter (ng*h/mL)]	NA (NA)	NA (NA)	NA (NA)	NA (NA)

6. Secondary Outcome

Title	Part A: Maximum Observed Plasma Concentration (Cmax) of VX-984
Description	Pharmacokinetic PK parameter Cmax was obtained directly from the concentration versus time curve.
Time Frame	Pre-dose and at 0.5, 1, 2, 4, 8, and 24 hours post-dose on Day -12 and Day 4 in Cycle 1; Pre-dose and at 0.5, 1, 2, 4 hours post-dose on Day 2 in Cycle 1 (each Cycle is of 28 days)

Outcome Measure Data

Analysis Population Description

The Pharmacokinetic (PK) analysis included all participants who had received at least 1 dose of VX-984 or PLD and provided at least 1 measurable post dose concentration of VX-984 or one measurable post dose concentration of PLD.

Arm/Group Title	VX-984 120 mg + PLD 40 mg/m^2	VX-984 240 mg + PLD 40 mg/m^2	VX-984 480 mg + PLD 40 mg/m^2	VX-984 720 mg + PLD 40 mg/m^2
Arm/Group Description	Participants received VX-984 orally 120 milligram (mg) once daily alone on Days -14 to -12 of a 14-day Lead-in Period, followed by VX-984 120 mg in combination with pegylated liposomal doxorubicin (PLD) 40 milligram per square meter (mg/m^2) administered intravenous infusion, with PLD administered on Day 1 and VX-984 administered on Day 2 to Day 4 for up to six 28-day cycle or until disease progression unacceptable toxicities withdrawal of consent, or until exposure to PLD exceeded 550 mg/m^2.	Participants received VX-984 orally 240 mg orally once daily alone on Days -14 to -12 of a 14-day Lead-in Period, followed by VX-984 240 mg in combination with PLD 40 mg/m^2 administered intravenous infusion, with PLD administered on Day 1 and VX-984 administered on Day 2 to Day 4 for up to six 28-day cycle or until disease progression unacceptable toxicities, withdrawal of consent, or until exposure to PLD exceeded 550 mg/m^2.	Participants received VX-984 orally 480 mg orally once daily alone on Days -14 to -12 of a 14-day Lead-in Period, followed by VX-984 480 mg in combination with PLD 40 mg/m^2 administered intravenous infusion, with PLD administered on Day 1 and VX-984 administered on Day 2 to Day 4 for up to six 28-day cycle or until disease progression unacceptable toxicities, withdrawal of consent, or until exposure to PLD exceeded 550 mg/m^2.	Participants received VX-984 orally 720 mg orally once daily alone on Days -14 to -12 of a 14-day Lead-in Period, followed by VX-984 720 mg in combination with PLD 40 mg/m^2 administered intravenous infusion, with PLD administered on Day 1 and VX-984 administered on Day 2 to Day 4 for up to six 28-day cycle or until disease progression unacceptable toxicities, withdrawal of consent, or until exposure to PLD exceeded 550 mg/m^2.
Measure Participants	3	3	6	3
Geometric Mean (Geometric Coefficient of Variation) [ng/mL]	NA (NA)	NA (NA)	NA (NA)	NA (NA)

7. Secondary Outcome

Title	Part A: Time to Reach Maximum Plasma Concentration (Tmax) of VX-984
Description	Time to reach the maximum plasma concentration (Tmax) was obtained directly from the concentration versus time curve.
Time Frame	Pre-dose and at 0.5, 1, 2, 4, 8, and 24 hours post-dose on Day -12 and Day 4 in Cycle 1; Pre-dose and at 0.5, 1, 2, 4 hours post-dose on Day 2 in Cycle 1 (each Cycle is of 28 days)

Outcome Measure Data

Analysis Population Description

The Pharmacokinetic (PK) analysis included all participants who had received at least 1 dose of VX-984 or PLD and provided at least 1 measurable post dose concentration of VX-984 or one measurable post dose concentration of PLD.

Arm/Group Title	VX-984 120 mg + PLD 40 mg/m^2	VX-984 240 mg + PLD 40 mg/m^2	VX-984 480 mg + PLD 40 mg/m^2	VX-984 720 mg + PLD 40 mg/m^2
Arm/Group Description	Participants received VX-984 orally 120 milligram (mg) once daily alone on Days -14 to -12 of a 14-day Lead-in Period, followed by VX-984 120 mg in combination with pegylated liposomal doxorubicin (PLD) 40 milligram per square meter (mg/m^2) administered intravenous infusion, with PLD administered on Day 1 and VX-984 administered on Day 2 to Day 4 for up to six 28-day cycle or until disease progression unacceptable toxicities withdrawal of consent, or until exposure to PLD exceeded 550 mg/m^2.	Participants received VX-984 orally 240 mg orally once daily alone on Days -14 to -12 of a 14-day Lead-in Period, followed by VX-984 240 mg in combination with PLD 40 mg/m^2 administered intravenous infusion, with PLD administered on Day 1 and VX-984 administered on Day 2 to Day 4 for up to six 28-day cycle or until disease progression unacceptable toxicities, withdrawal of consent, or until exposure to PLD exceeded 550 mg/m^2.	Participants received VX-984 orally 480 mg orally once daily alone on Days -14 to -12 of a 14-day Lead-in Period, followed by VX-984 480 mg in combination with PLD 40 mg/m^2 administered intravenous infusion, with PLD administered on Day 1 and VX-984 administered on Day 2 to Day 4 for up to six 28-day cycle or until disease progression unacceptable toxicities, withdrawal of consent, or until exposure to PLD exceeded 550 mg/m^2.	Participants received VX-984 orally 720 mg orally once daily alone on Days -14 to -12 of a 14-day Lead-in Period, followed by VX-984 720 mg in combination with PLD 40 mg/m^2 administered intravenous infusion, with PLD administered on Day 1 and VX-984 administered on Day 2 to Day 4 for up to six 28-day cycle or until disease progression unacceptable toxicities, withdrawal of consent, or until exposure to PLD exceeded 550 mg/m^2.
Measure Participants	3	3	6	3
Median (Full Range) [hours]	NA	NA	NA	NA

8. Secondary Outcome

Title	Part A: Minimum Observed Plasma Concentration During Dosing Interval (Cmin) of VX-984
Description	Cmin is minimum observed plasma concentration obtained directly from the concentration versus time curve.
Time Frame	Pre-dose and at 0.5, 1, 2, 4, 8, and 24 hours post-dose on Day -12 and Day 4 in Cycle 1; Pre-dose and at 0.5, 1, 2, 4 hours post-dose on Day 2 in Cycle 1 (each Cycle is of 28 days)

Outcome Measure Data

Analysis Population Description

The Pharmacokinetic (PK) analysis included all participants who had received at least 1 dose of VX-984 or PLD and provided at least 1 measurable post dose concentration of VX-984 or one measurable post dose concentration of PLD.

Arm/Group Title	VX-984 120 mg + PLD 40 mg/m^2	VX-984 240 mg + PLD 40 mg/m^2	VX-984 480 mg + PLD 40 mg/m^2	VX-984 720 mg + PLD 40 mg/m^2
Arm/Group Description	Participants received VX-984 orally 120 milligram (mg) once daily alone on Days -14 to -12 of a 14-day Lead-in Period, followed by VX-984 120 mg in combination with pegylated liposomal doxorubicin (PLD) 40 milligram per square meter (mg/m^2) administered intravenous infusion, with PLD administered on Day 1 and VX-984 administered on Day 2 to Day 4 for up to six 28-day cycle or until disease progression unacceptable toxicities withdrawal of consent, or until exposure to PLD exceeded 550 mg/m^2.	Participants received VX-984 orally 240 mg orally once daily alone on Days -14 to -12 of a 14-day Lead-in Period, followed by VX-984 240 mg in combination with PLD 40 mg/m^2 administered intravenous infusion, with PLD administered on Day 1 and VX-984 administered on Day 2 to Day 4 for up to six 28-day cycle or until disease progression unacceptable toxicities, withdrawal of consent, or until exposure to PLD exceeded 550 mg/m^2.	Participants received VX-984 orally 480 mg orally once daily alone on Days -14 to -12 of a 14-day Lead-in Period, followed by VX-984 480 mg in combination with PLD 40 mg/m^2 administered intravenous infusion, with PLD administered on Day 1 and VX-984 administered on Day 2 to Day 4 for up to six 28-day cycle or until disease progression unacceptable toxicities, withdrawal of consent, or until exposure to PLD exceeded 550 mg/m^2.	Participants received VX-984 orally 720 mg orally once daily alone on Days -14 to -12 of a 14-day Lead-in Period, followed by VX-984 720 mg in combination with PLD 40 mg/m^2 administered intravenous infusion, with PLD administered on Day 1 and VX-984 administered on Day 2 to Day 4 for up to six 28-day cycle or until disease progression unacceptable toxicities, withdrawal of consent, or until exposure to PLD exceeded 550 mg/m^2.
Measure Participants	3	3	6	3
Geometric Mean (Geometric Coefficient of Variation) [ng/mL]	NA (NA)	NA (NA)	NA (NA)	NA (NA)

9. Secondary Outcome

Title	Part A: Area Under the Plasma Concentration Curve From Time Zero to 96 Hours Post Dose AUC(0-96h) of Pegylated Liposomal Doxorubicin
Description	The AUC(0-96h) was estimated by determining the total area under the curve of the concentration versus curve extrapolated from 0 to 96 hours.
Time Frame	Pre-infusion and at 1, 2, 4, 6, 24, 72 and 96 hours after infusion in Cycle 1 (each Cycle is of 28 days)

Outcome Measure Data

Analysis Population Description

The Pharmacokinetic (PK) analysis included all participants who had received at least 1 dose of VX-984 or PLD and provided at least 1 measurable post dose concentration of VX-984 or one measurable post dose concentration of PLD.

Arm/Group Title	VX-984 120 mg + PLD 40 mg/m^2	VX-984 240 mg + PLD 40 mg/m^2	VX-984 480 mg + PLD 40 mg/m^2	VX-984 720 mg + PLD 40 mg/m^2
Arm/Group Description	Participants received VX-984 orally 120 milligram (mg) once daily alone on Days -14 to -12 of a 14-day Lead-in Period, followed by VX-984 120 mg in combination with pegylated liposomal doxorubicin (PLD) 40 milligram per square meter (mg/m^2) administered intravenous infusion, with PLD administered on Day 1 and VX-984 administered on Day 2 to Day 4 for up to six 28-day cycle or until disease progression unacceptable toxicities withdrawal of consent, or until exposure to PLD exceeded 550 mg/m^2.	Participants received VX-984 orally 240 mg orally once daily alone on Days -14 to -12 of a 14-day Lead-in Period, followed by VX-984 240 mg in combination with PLD 40 mg/m^2 administered intravenous infusion, with PLD administered on Day 1 and VX-984 administered on Day 2 to Day 4 for up to six 28-day cycle or until disease progression unacceptable toxicities, withdrawal of consent, or until exposure to PLD exceeded 550 mg/m^2.	Participants received VX-984 orally 480 mg orally once daily alone on Days -14 to -12 of a 14-day Lead-in Period, followed by VX-984 480 mg in combination with PLD 40 mg/m^2 administered intravenous infusion, with PLD administered on Day 1 and VX-984 administered on Day 2 to Day 4 for up to six 28-day cycle or until disease progression unacceptable toxicities, withdrawal of consent, or until exposure to PLD exceeded 550 mg/m^2.	Participants received VX-984 orally 720 mg orally once daily alone on Days -14 to -12 of a 14-day Lead-in Period, followed by VX-984 720 mg in combination with PLD 40 mg/m^2 administered intravenous infusion, with PLD administered on Day 1 and VX-984 administered on Day 2 to Day 4 for up to six 28-day cycle or until disease progression unacceptable toxicities, withdrawal of consent, or until exposure to PLD exceeded 550 mg/m^2.
Measure Participants	3	3	6	3
Geometric Mean (Geometric Coefficient of Variation) [ng*h/mL]	NA (NA)	NA (NA)	NA (NA)	NA (NA)

10. Secondary Outcome

Title	Part A: Maximum Observed Plasma Concentration (Cmax0-96h) From Time Zero to 96 Hours Post Dose of Pegylated Liposomal Doxorubicin
Description	Cmax is the maximum observed plasma concentration obtained directly from concentration versus time curve from zero to 96 hours
Time Frame	Pre-infusion and at 1, 2, 4, 6, 24, 72 and 96 hours after infusion in Cycle 1 (each Cycle is of 28 days)

Outcome Measure Data

Analysis Population Description

The Pharmacokinetic (PK) analysis included all participants who had received at least 1 dose of VX-984 or PLD and provided at least 1 measurable post dose concentration of VX-984 or one measurable post dose concentration of PLD.

Arm/Group Title	VX-984 120 mg + PLD 40 mg/m^2	VX-984 240 mg + PLD 40 mg/m^2	VX-984 480 mg + PLD 40 mg/m^2	VX-984 720 mg + PLD 40 mg/m^2
Arm/Group Description	Participants received VX-984 orally 120 milligram (mg) once daily alone on Days -14 to -12 of a 14-day Lead-in Period, followed by VX-984 120 mg in combination with pegylated liposomal doxorubicin (PLD) 40 milligram per square meter (mg/m^2) administered intravenous infusion, with PLD administered on Day 1 and VX-984 administered on Day 2 to Day 4 for up to six 28-day cycle or until disease progression unacceptable toxicities withdrawal of consent, or until exposure to PLD exceeded 550 mg/m^2.	Participants received VX-984 orally 240 mg orally once daily alone on Days -14 to -12 of a 14-day Lead-in Period, followed by VX-984 240 mg in combination with PLD 40 mg/m^2 administered intravenous infusion, with PLD administered on Day 1 and VX-984 administered on Day 2 to Day 4 for up to six 28-day cycle or until disease progression unacceptable toxicities, withdrawal of consent, or until exposure to PLD exceeded 550 mg/m^2.	Participants received VX-984 orally 480 mg orally once daily alone on Days -14 to -12 of a 14-day Lead-in Period, followed by VX-984 480 mg in combination with PLD 40 mg/m^2 administered intravenous infusion, with PLD administered on Day 1 and VX-984 administered on Day 2 to Day 4 for up to six 28-day cycle or until disease progression unacceptable toxicities, withdrawal of consent, or until exposure to PLD exceeded 550 mg/m^2.	Participants received VX-984 orally 720 mg orally once daily alone on Days -14 to -12 of a 14-day Lead-in Period, followed by VX-984 720 mg in combination with PLD 40 mg/m^2 administered intravenous infusion, with PLD administered on Day 1 and VX-984 administered on Day 2 to Day 4 for up to six 28-day cycle or until disease progression unacceptable toxicities, withdrawal of consent, or until exposure to PLD exceeded 550 mg/m^2.
Measure Participants	3	3	6	3
Geometric Mean (Geometric Coefficient of Variation) [ng/mL]	NA (NA)	NA (NA)	NA (NA)	NA (NA)

11. Secondary Outcome

Title	Part A: Time to Reach Maximum Plasma Concentration From Zero to 96 Hours Post Dose (tmax0-96h) of Pegylated Liposomal Doxorubicin
Description	Tmax is time to reach maximum observed plasma concentration obtained directly from the concentration versus time curve from zero to 96 hours post dose.
Time Frame	Pre-infusion and at 1, 2, 4, 6, 24, 72 and 96 hours after infusion in Cycle 1 (each Cycle is of 28 days)

Outcome Measure Data

Analysis Population Description

The Pharmacokinetic (PK) analysis included all participants who had received at least 1 dose of VX-984 or PLD and provided at least 1 measurable post dose concentration of VX-984 or one measurable post dose concentration of PLD.

Arm/Group Title	VX-984 120 mg + PLD 40 mg/m^2	VX-984 240 mg + PLD 40 mg/m^2	VX-984 480 mg + PLD 40 mg/m^2	VX-984 720 mg + PLD 40 mg/m^2
Arm/Group Description	Participants received VX-984 orally 120 milligram (mg) once daily alone on Days -14 to -12 of a 14-day Lead-in Period, followed by VX-984 120 mg in combination with pegylated liposomal doxorubicin (PLD) 40 milligram per square meter (mg/m^2) administered intravenous infusion, with PLD administered on Day 1 and VX-984 administered on Day 2 to Day 4 for up to six 28-day cycle or until disease progression unacceptable toxicities withdrawal of consent, or until exposure to PLD exceeded 550 mg/m^2.	Participants received VX-984 orally 240 mg orally once daily alone on Days -14 to -12 of a 14-day Lead-in Period, followed by VX-984 240 mg in combination with PLD 40 mg/m^2 administered intravenous infusion, with PLD administered on Day 1 and VX-984 administered on Day 2 to Day 4 for up to six 28-day cycle or until disease progression unacceptable toxicities, withdrawal of consent, or until exposure to PLD exceeded 550 mg/m^2.	Participants received VX-984 orally 480 mg orally once daily alone on Days -14 to -12 of a 14-day Lead-in Period, followed by VX-984 480 mg in combination with PLD 40 mg/m^2 administered intravenous infusion, with PLD administered on Day 1 and VX-984 administered on Day 2 to Day 4 for up to six 28-day cycle or until disease progression unacceptable toxicities, withdrawal of consent, or until exposure to PLD exceeded 550 mg/m^2.	Participants received VX-984 orally 720 mg orally once daily alone on Days -14 to -12 of a 14-day Lead-in Period, followed by VX-984 720 mg in combination with PLD 40 mg/m^2 administered intravenous infusion, with PLD administered on Day 1 and VX-984 administered on Day 2 to Day 4 for up to six 28-day cycle or until disease progression unacceptable toxicities, withdrawal of consent, or until exposure to PLD exceeded 550 mg/m^2.
Measure Participants	3	3	6	3
Median (Full Range) [Hours]	NA	NA	NA	NA

12. Secondary Outcome

Title	Part A: Number of Participants With Best Overall Response Evaluated by Response Criteria Evaluation (RECIST 1.1)
Description	The best overall response was defined as the number of participants who had achieved complete response (CR) or partial response (PR) as the best overall response according to radiological assessments as adjudicated by the IRC from randomization until the first occurrence of progressive disease (PD). CR: Complete Response (CR) defined as disappearance of all target and non-target lesions and any pathological lymph nodes (whether target or non-target) must have reduction in short axis to < 10 mm. Partial response (PR) defined as at least a 30% decrease in the sum of diameters of target lesions taking as reference the baseline sum diameters. PD defined as an increase of at least 20% in the sum of the diameters of target lesions, taking as reference the smallest sum of the diameters of target lesions recorded since treatment started.
Time Frame	Up to 2 years

Outcome Measure Data

Analysis Population Description

Full analysis set included all participants who had received at least 1 dose of the study treatment.

Arm/Group Title	VX-984 120 mg + PLD 40 mg/m^2	VX-984 240 mg + PLD 40 mg/m^2	VX-984 480 mg + PLD 40 mg/m^2	VX-984 720 mg + PLD 40 mg/m^2
Arm/Group Description	Participants received VX-984 orally 120 milligram (mg) once daily alone on Days -14 to -12 of a 14-day Lead-in Period, followed by VX-984 120 mg in combination with pegylated liposomal doxorubicin (PLD) 40 milligram per square meter (mg/m^2) administered intravenous infusion, with PLD administered on Day 1 and VX-984 administered on Day 2 to Day 4 for up to six 28-day cycle or until disease progression unacceptable toxicities withdrawal of consent, or until exposure to PLD exceeded 550 mg/m^2.	Participants received VX-984 orally 240 mg orally once daily alone on Days -14 to -12 of a 14-day Lead-in Period, followed by VX-984 240 mg in combination with PLD 40 mg/m^2 administered intravenous infusion, with PLD administered on Day 1 and VX-984 administered on Day 2 to Day 4 for up to six 28-day cycle or until disease progression unacceptable toxicities, withdrawal of consent, or until exposure to PLD exceeded 550 mg/m^2.	Participants received VX-984 orally 480 mg orally once daily alone on Days -14 to -12 of a 14-day Lead-in Period, followed by VX-984 480 mg in combination with PLD 40 mg/m^2 administered intravenous infusion, with PLD administered on Day 1 and VX-984 administered on Day 2 to Day 4 for up to six 28-day cycle or until disease progression unacceptable toxicities, withdrawal of consent, or until exposure to PLD exceeded 550 mg/m^2.	Participants received VX-984 orally 720 mg orally once daily alone on Days -14 to -12 of a 14-day Lead-in Period, followed by VX-984 720 mg in combination with PLD 40 mg/m^2 administered intravenous infusion, with PLD administered on Day 1 and VX-984 administered on Day 2 to Day 4 for up to six 28-day cycle or until disease progression unacceptable toxicities, withdrawal of consent, or until exposure to PLD exceeded 550 mg/m^2.
Measure Participants	3	3	6	3
Complete Response	0 0%	0 0%	0 0%	0 0%
Partial Response	1 33.3%	0 0%	0 0%	0 0%
Stable disease	1 33.3%	0 0%	4 66.7%	1 33.3%
Progressive disease	0 0%	3 100%	0 0%	1 33.3%
Not evaluable	1 33.3%	0 0%	2 33.3%	1 33.3%

13. Primary Outcome

Title	Part A: Number of Participants With Clinical Significant Abnormalities in Vital Signs
Description	Vital signs assessment included blood pressure, pulse rate and body temperature. Clinical significance was determined by the investigator. Number of participants with clinical significant abnormalities in vital Signs reported here.
Time Frame	Baseline up to 28 days after the last dose of study treatment, assessed up to 53.1 weeks

Outcome Measure Data

Analysis Population Description

The safety analysis set included all participants who had received at least 1 dose of the study treatment.

Arm/Group Title	VX-984 120 mg + PLD 40 mg/m^2	VX-984 240 mg + PLD 40 mg/m^2	VX-984 480 mg + PLD 40 mg/m^2	VX-984 720 mg + PLD 40 mg/m^2
Arm/Group Description	Participants received VX-984 orally 120 milligram (mg) once daily alone on Days -14 to -12 of a 14-day Lead-in Period, followed by VX-984 120 mg in combination with pegylated liposomal doxorubicin (PLD) 40 milligram per square meter (mg/m^2) administered intravenous infusion, with PLD administered on Day 1 and VX-984 administered on Day 2 to Day 4 for up to six 28-day cycle or until disease progression unacceptable toxicities withdrawal of consent, or until exposure to PLD exceeded 550 mg/m^2.	Participants received VX-984 orally 240 mg orally once daily alone on Days -14 to -12 of a 14-day Lead-in Period, followed by VX-984 240 mg in combination with PLD 40 mg/m^2 administered intravenous infusion, with PLD administered on Day 1 and VX-984 administered on Day 2 to Day 4 for up to six 28-day cycle or until disease progression unacceptable toxicities, withdrawal of consent, or until exposure to PLD exceeded 550 mg/m^2.	Participants received VX-984 orally 480 mg orally once daily alone on Days -14 to -12 of a 14-day Lead-in Period, followed by VX-984 480 mg in combination with PLD 40 mg/m^2 administered intravenous infusion, with PLD administered on Day 1 and VX-984 administered on Day 2 to Day 4 for up to six 28-day cycle or until disease progression unacceptable toxicities, withdrawal of consent, or until exposure to PLD exceeded 550 mg/m^2.	Participants received VX-984 orally 720 mg orally once daily alone on Days -14 to -12 of a 14-day Lead-in Period, followed by VX-984 720 mg in combination with PLD 40 mg/m^2 administered intravenous infusion, with PLD administered on Day 1 and VX-984 administered on Day 2 to Day 4 for up to six 28-day cycle or until disease progression unacceptable toxicities, withdrawal of consent, or until exposure to PLD exceeded 550 mg/m^2.
Measure Participants	3	3	6	3
Count of Participants [Participants]	0 0%	0 0%	0 0%	0 0%

14. Primary Outcome

Title	Part A: Number of Participants With Clinical Significant Abnormalities Echocardiograms
Description	Echocardiogram is a graphic outline of the heart's movement. Clinical significance was determined by the investigator. Number of participants with clinical significant abnormalities in Echocardiograms reported here.
Time Frame	Baseline up to 28 days after the last dose of study treatment, assessed up to 53.1 weeks

Outcome Measure Data

Analysis Population Description

The safety analysis set included all participants who had received at least 1 dose of the study treatment.

Arm/Group Title	VX-984 120 mg + PLD 40 mg/m^2	VX-984 240 mg + PLD 40 mg/m^2	VX-984 480 mg + PLD 40 mg/m^2	VX-984 720 mg + PLD 40 mg/m^2
Arm/Group Description	Participants received VX-984 orally 120 milligram (mg) once daily alone on Days -14 to -12 of a 14-day Lead-in Period, followed by VX-984 120 mg in combination with pegylated liposomal doxorubicin (PLD) 40 milligram per square meter (mg/m^2) administered intravenous infusion, with PLD administered on Day 1 and VX-984 administered on Day 2 to Day 4 for up to six 28-day cycle or until disease progression unacceptable toxicities withdrawal of consent, or until exposure to PLD exceeded 550 mg/m^2.	Participants received VX-984 orally 240 mg orally once daily alone on Days -14 to -12 of a 14-day Lead-in Period, followed by VX-984 240 mg in combination with PLD 40 mg/m^2 administered intravenous infusion, with PLD administered on Day 1 and VX-984 administered on Day 2 to Day 4 for up to six 28-day cycle or until disease progression unacceptable toxicities, withdrawal of consent, or until exposure to PLD exceeded 550 mg/m^2.	Participants received VX-984 orally 480 mg orally once daily alone on Days -14 to -12 of a 14-day Lead-in Period, followed by VX-984 480 mg in combination with PLD 40 mg/m^2 administered intravenous infusion, with PLD administered on Day 1 and VX-984 administered on Day 2 to Day 4 for up to six 28-day cycle or until disease progression unacceptable toxicities, withdrawal of consent, or until exposure to PLD exceeded 550 mg/m^2.	Participants received VX-984 orally 720 mg orally once daily alone on Days -14 to -12 of a 14-day Lead-in Period, followed by VX-984 720 mg in combination with PLD 40 mg/m^2 administered intravenous infusion, with PLD administered on Day 1 and VX-984 administered on Day 2 to Day 4 for up to six 28-day cycle or until disease progression unacceptable toxicities, withdrawal of consent, or until exposure to PLD exceeded 550 mg/m^2.
Measure Participants	3	3	6	3
Count of Participants [Participants]	0 0%	0 0%	0 0%	0 0%

15. Primary Outcome

Title	Part A: Number of Participants With Clinical Significant Abnormalities in Electrocardiogram(ECG) Parameters
Description	ECG parameters included heart rate, pulse rate, QRS,QT, RR, QTcB and QTcF. Clinical significance was determined by the investigator. Number of participants with clinical significant abnormalities in ECG parameters reported here.
Time Frame	Baseline up to 28 days after the last dose of study treatment, assessed up to 53.1 weeks

Outcome Measure Data

Analysis Population Description

The safety analysis set included all participants who had received at least 1 dose of the study treatment.

Arm/Group Title	VX-984 120 mg + PLD 40 mg/m^2	VX-984 240 mg + PLD 40 mg/m^2	VX-984 480 mg + PLD 40 mg/m^2	VX-984 720 mg + PLD 40 mg/m^2
Arm/Group Description	Participants received VX-984 orally 120 milligram (mg) once daily alone on Days -14 to -12 of a 14-day Lead-in Period, followed by VX-984 120 mg in combination with pegylated liposomal doxorubicin (PLD) 40 milligram per square meter (mg/m^2) administered intravenous infusion, with PLD administered on Day 1 and VX-984 administered on Day 2 to Day 4 for up to six 28-day cycle or until disease progression unacceptable toxicities withdrawal of consent, or until exposure to PLD exceeded 550 mg/m^2.	Participants received VX-984 orally 240 mg orally once daily alone on Days -14 to -12 of a 14-day Lead-in Period, followed by VX-984 240 mg in combination with PLD 40 mg/m^2 administered intravenous infusion, with PLD administered on Day 1 and VX-984 administered on Day 2 to Day 4 for up to six 28-day cycle or until disease progression unacceptable toxicities, withdrawal of consent, or until exposure to PLD exceeded 550 mg/m^2.	Participants received VX-984 orally 480 mg orally once daily alone on Days -14 to -12 of a 14-day Lead-in Period, followed by VX-984 480 mg in combination with PLD 40 mg/m^2 administered intravenous infusion, with PLD administered on Day 1 and VX-984 administered on Day 2 to Day 4 for up to six 28-day cycle or until disease progression unacceptable toxicities, withdrawal of consent, or until exposure to PLD exceeded 550 mg/m^2.	Participants received VX-984 orally 720 mg orally once daily alone on Days -14 to -12 of a 14-day Lead-in Period, followed by VX-984 720 mg in combination with PLD 40 mg/m^2 administered intravenous infusion, with PLD administered on Day 1 and VX-984 administered on Day 2 to Day 4 for up to six 28-day cycle or until disease progression unacceptable toxicities, withdrawal of consent, or until exposure to PLD exceeded 550 mg/m^2.
Measure Participants	3	3	6	3
Count of Participants [Participants]	0 0%	0 0%	0 0%	0 0%

Adverse Events

Time Frame	Baseline up to 28 days of follow up after the last dose of study treatment, assessed up to 53.1 weeks
Arm/Group Title	VX-984 120 mg + PLD 40 mg/m^2		VX-984 240 mg + PLD 40 mg/m^2		VX-984 480 mg + PLD 40 mg/m^2		VX-984 720 mg + PLD 40 mg/m^2
Arm/Group Description	Participants received VX-984 orally 120 milligram (mg) once daily alone on Days -14 to -12 of a 14-day Lead-in Period, followed by VX-984 120 mg in combination with pegylated liposomal doxorubicin (PLD) 40 milligram per square meter (mg/m^2) administered intravenous infusion, with PLD administered on Day 1 and VX-984 administered on Day 2 to Day 4 for up to six 28-day cycle or until disease progression unacceptable toxicities withdrawal of consent, or until exposure to PLD exceeded 550 mg/m^2.		Participants received VX-984 orally 240 mg orally once daily alone on Days -14 to -12 of a 14-day Lead-in Period, followed by VX-984 240 mg in combination with PLD 40 mg/m^2 administered intravenous infusion, with PLD administered on Day 1 and VX-984 administered on Day 2 to Day 4 for up to six 28-day cycle or until disease progression unacceptable toxicities, withdrawal of consent, or until exposure to PLD exceeded 550 mg/m^2.		Participants received VX-984 orally 480 mg orally once daily alone on Days -14 to -12 of a 14-day Lead-in Period, followed by VX-984 480 mg in combination with PLD 40 mg/m^2 administered intravenous infusion, with PLD administered on Day 1 and VX-984 administered on Day 2 to Day 4 for up to six 28-day cycle or until disease progression unacceptable toxicities, withdrawal of consent, or until exposure to PLD exceeded 550 mg/m^2.		Participants received VX-984 orally 720 mg orally once daily alone on Days -14 to -12 of a 14-day Lead-in Period, followed by VX-984 720 mg in combination with PLD 40 mg/m^2 administered intravenous infusion, with PLD administered on Day 1 and VX-984 administered on Day 2 to Day 4 for up to six 28-day cycle or until disease progression unacceptable toxicities, withdrawal of consent, or until exposure to PLD exceeded 550 mg/m^2.
All Cause Mortality
	VX-984 120 mg + PLD 40 mg/m^2		VX-984 240 mg + PLD 40 mg/m^2		VX-984 480 mg + PLD 40 mg/m^2		VX-984 720 mg + PLD 40 mg/m^2
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/3 (0%)		0/3 (0%)		2/6 (33.3%)		0/3 (0%)
Serious Adverse Events
	VX-984 120 mg + PLD 40 mg/m^2		VX-984 240 mg + PLD 40 mg/m^2		VX-984 480 mg + PLD 40 mg/m^2		VX-984 720 mg + PLD 40 mg/m^2
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/3 (66.7%)		0/3 (0%)		3/6 (50%)		1/3 (33.3%)
Gastrointestinal disorders
Abdominal pain	2/3 (66.7%)		0/3 (0%)		0/6 (0%)		0/3 (0%)
Nausea	1/3 (33.3%)		0/3 (0%)		1/6 (16.7%)		0/3 (0%)
Small intestinal obstruction	1/3 (33.3%)		0/3 (0%)		0/6 (0%)		1/3 (33.3%)
Infections and infestations
Lung infection	0/3 (0%)		0/3 (0%)		1/6 (16.7%)		0/3 (0%)
Sepsis	0/3 (0%)		0/3 (0%)		1/6 (16.7%)		0/3 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Cancer pain	1/3 (33.3%)		0/3 (0%)		0/6 (0%)		0/3 (0%)
Respiratory, thoracic and mediastinal disorders
Pleural effusion	0/3 (0%)		0/3 (0%)		1/6 (16.7%)		0/3 (0%)
Pulmonary embolism	0/3 (0%)		0/3 (0%)		1/6 (16.7%)		0/3 (0%)
Vascular disorders
Deep vein thrombosis	0/3 (0%)		0/3 (0%)		1/6 (16.7%)		0/3 (0%)
Other (Not Including Serious) Adverse Events
	VX-984 120 mg + PLD 40 mg/m^2		VX-984 240 mg + PLD 40 mg/m^2		VX-984 480 mg + PLD 40 mg/m^2		VX-984 720 mg + PLD 40 mg/m^2
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/3 (100%)		3/3 (100%)		6/6 (100%)		3/3 (100%)
Blood and lymphatic system disorders
Anaemia	1/3 (33.3%)		0/3 (0%)		2/6 (33.3%)		1/3 (33.3%)
Iron deficiency anaemia	0/3 (0%)		1/3 (33.3%)		1/6 (16.7%)		0/3 (0%)
Leukocytosis	0/3 (0%)		0/3 (0%)		1/6 (16.7%)		0/3 (0%)
Leukopenia	0/3 (0%)		0/3 (0%)		0/6 (0%)		1/3 (33.3%)
Neutropenia	0/3 (0%)		0/3 (0%)		2/6 (33.3%)		2/3 (66.7%)
Thrombocytopenia	0/3 (0%)		0/3 (0%)		1/6 (16.7%)		1/3 (33.3%)
Cardiac disorders
Sinus bradycardia	0/3 (0%)		1/3 (33.3%)		0/6 (0%)		0/3 (0%)
Ear and labyrinth disorders
Vertigo	0/3 (0%)		0/3 (0%)		1/6 (16.7%)		0/3 (0%)
Eye disorders
Vision blurred	0/3 (0%)		1/3 (33.3%)		0/6 (0%)		0/3 (0%)
Gastrointestinal disorders
Abdominal discomfort	1/3 (33.3%)		0/3 (0%)		0/6 (0%)		0/3 (0%)
Abdominal distension	0/3 (0%)		1/3 (33.3%)		1/6 (16.7%)		2/3 (66.7%)
Abdominal pain	1/3 (33.3%)		1/3 (33.3%)		1/6 (16.7%)		0/3 (0%)
Abdominal pain upper	1/3 (33.3%)		1/3 (33.3%)		1/6 (16.7%)		0/3 (0%)
Colitis	1/3 (33.3%)		0/3 (0%)		0/6 (0%)		0/3 (0%)
Constipation	2/3 (66.7%)		2/3 (66.7%)		1/6 (16.7%)		1/3 (33.3%)
Diarrhoea	0/3 (0%)		1/3 (33.3%)		1/6 (16.7%)		2/3 (66.7%)
Dyspepsia	0/3 (0%)		1/3 (33.3%)		2/6 (33.3%)		1/3 (33.3%)
Dysphagia	1/3 (33.3%)		0/3 (0%)		0/6 (0%)		0/3 (0%)
Flatulence	0/3 (0%)		0/3 (0%)		1/6 (16.7%)		0/3 (0%)
Gastric ulcer	1/3 (33.3%)		0/3 (0%)		0/6 (0%)		0/3 (0%)
Gastrointestinal haemorrhage	0/3 (0%)		0/3 (0%)		1/6 (16.7%)		0/3 (0%)
Gastrooesophageal reflux disease	0/3 (0%)		0/3 (0%)		2/6 (33.3%)		0/3 (0%)
Haemorrhoids	0/3 (0%)		0/3 (0%)		2/6 (33.3%)		0/3 (0%)
Nausea	1/3 (33.3%)		2/3 (66.7%)		4/6 (66.7%)		3/3 (100%)
Stomatitis	1/3 (33.3%)		2/3 (66.7%)		2/6 (33.3%)		1/3 (33.3%)
Vomiting	2/3 (66.7%)		1/3 (33.3%)		4/6 (66.7%)		2/3 (66.7%)
General disorders
Asthenia	0/3 (0%)		1/3 (33.3%)		2/6 (33.3%)		0/3 (0%)
Fatigue	2/3 (66.7%)		2/3 (66.7%)		2/6 (33.3%)		3/3 (100%)
Mucosal inflammation	0/3 (0%)		0/3 (0%)		0/6 (0%)		1/3 (33.3%)
Non-cardiac chest pain	2/3 (66.7%)		0/3 (0%)		0/6 (0%)		0/3 (0%)
Oedema peripheral	0/3 (0%)		0/3 (0%)		0/6 (0%)		1/3 (33.3%)
Pyrexia	2/3 (66.7%)		0/3 (0%)		1/6 (16.7%)		0/3 (0%)
Temperature intolerance	0/3 (0%)		0/3 (0%)		1/6 (16.7%)		0/3 (0%)
Infections and infestations
Fungal skin infection	0/3 (0%)		0/3 (0%)		1/6 (16.7%)		0/3 (0%)
Infection	0/3 (0%)		0/3 (0%)		1/6 (16.7%)		0/3 (0%)
Lung infection	0/3 (0%)		0/3 (0%)		1/6 (16.7%)		0/3 (0%)
Oral candidiasis	1/3 (33.3%)		0/3 (0%)		0/6 (0%)		0/3 (0%)
Pneumonia	0/3 (0%)		0/3 (0%)		1/6 (16.7%)		0/3 (0%)
Pyelonephritis	1/3 (33.3%)		0/3 (0%)		0/6 (0%)		0/3 (0%)
Sepsis	0/3 (0%)		0/3 (0%)		1/6 (16.7%)		0/3 (0%)
Upper respiratory tract infection	0/3 (0%)		1/3 (33.3%)		0/6 (0%)		0/3 (0%)
Urinary tract infection	1/3 (33.3%)		0/3 (0%)		1/6 (16.7%)		0/3 (0%)
Injury, poisoning and procedural complications
Fall	0/3 (0%)		0/3 (0%)		1/6 (16.7%)		0/3 (0%)
Infusion related reaction	0/3 (0%)		0/3 (0%)		1/6 (16.7%)		0/3 (0%)
Investigations
Aspartate aminotransferase increased	0/3 (0%)		1/3 (33.3%)		0/6 (0%)		0/3 (0%)
Blood cholesterol increased	0/3 (0%)		0/3 (0%)		1/6 (16.7%)		0/3 (0%)
Lymphocyte count decreased	0/3 (0%)		0/3 (0%)		1/6 (16.7%)		0/3 (0%)
Weight decreased	0/3 (0%)		0/3 (0%)		1/6 (16.7%)		0/3 (0%)
Metabolism and nutrition disorders
Decreased appetite	2/3 (66.7%)		2/3 (66.7%)		4/6 (66.7%)		2/3 (66.7%)
Dehydration	1/3 (33.3%)		1/3 (33.3%)		2/6 (33.3%)		0/3 (0%)
Hypertriglyceridaemia	0/3 (0%)		0/3 (0%)		1/6 (16.7%)		0/3 (0%)
Hypocalcaemia	0/3 (0%)		1/3 (33.3%)		0/6 (0%)		1/3 (33.3%)
Hypokalaemia	0/3 (0%)		0/3 (0%)		0/6 (0%)		1/3 (33.3%)
Hypomagnesaemia	1/3 (33.3%)		0/3 (0%)		0/6 (0%)		0/3 (0%)
Hyponatraemia	0/3 (0%)		1/3 (33.3%)		0/6 (0%)		0/3 (0%)
Musculoskeletal and connective tissue disorders
Back pain	0/3 (0%)		1/3 (33.3%)		0/6 (0%)		0/3 (0%)
Flank pain	1/3 (33.3%)		0/3 (0%)		0/6 (0%)		0/3 (0%)
Muscle tightness	1/3 (33.3%)		0/3 (0%)		0/6 (0%)		0/3 (0%)
Musculoskeletal chest pain	0/3 (0%)		1/3 (33.3%)		0/6 (0%)		0/3 (0%)
Pain in extremity	0/3 (0%)		1/3 (33.3%)		0/6 (0%)		0/3 (0%)
Soft tissue swelling	1/3 (33.3%)		0/3 (0%)		0/6 (0%)		0/3 (0%)
Nervous system disorders
Dysgeusia	0/3 (0%)		2/3 (66.7%)		0/6 (0%)		1/3 (33.3%)
Headache	0/3 (0%)		0/3 (0%)		1/6 (16.7%)		0/3 (0%)
Neuropathy peripheral	1/3 (33.3%)		1/3 (33.3%)		0/6 (0%)		0/3 (0%)
Peripheral sensory neuropathy	0/3 (0%)		0/3 (0%)		1/6 (16.7%)		0/3 (0%)
Somnolence	1/3 (33.3%)		0/3 (0%)		0/6 (0%)		0/3 (0%)
Psychiatric disorders
Delirium	0/3 (0%)		0/3 (0%)		1/6 (16.7%)		0/3 (0%)
Renal and urinary disorders
Bladder spasm	0/3 (0%)		0/3 (0%)		1/6 (16.7%)		0/3 (0%)
Chromaturia	0/3 (0%)		0/3 (0%)		1/6 (16.7%)		0/3 (0%)
Dysuria	1/3 (33.3%)		1/3 (33.3%)		0/6 (0%)		0/3 (0%)
Haematuria	1/3 (33.3%)		0/3 (0%)		0/6 (0%)		0/3 (0%)
Hydronephrosis	1/3 (33.3%)		1/3 (33.3%)		0/6 (0%)		0/3 (0%)
Pollakiuria	0/3 (0%)		1/3 (33.3%)		0/6 (0%)		1/3 (33.3%)
Urinary incontinence	0/3 (0%)		1/3 (33.3%)		0/6 (0%)		0/3 (0%)
Reproductive system and breast disorders
Dyspareunia	1/3 (33.3%)		0/3 (0%)		0/6 (0%)		0/3 (0%)
Vulvovaginal dryness	1/3 (33.3%)		0/3 (0%)		0/6 (0%)		0/3 (0%)
Respiratory, thoracic and mediastinal disorders
Cough	0/3 (0%)		1/3 (33.3%)		0/6 (0%)		0/3 (0%)
Dysphonia	0/3 (0%)		0/3 (0%)		1/6 (16.7%)		0/3 (0%)
Dyspnoea	1/3 (33.3%)		0/3 (0%)		1/6 (16.7%)		0/3 (0%)
Hiccups	0/3 (0%)		0/3 (0%)		0/6 (0%)		1/3 (33.3%)
Skin and subcutaneous tissue disorders
Alopecia	0/3 (0%)		1/3 (33.3%)		1/6 (16.7%)		0/3 (0%)
Dry skin	1/3 (33.3%)		0/3 (0%)		1/6 (16.7%)		0/3 (0%)
Nail bed disorder	1/3 (33.3%)		0/3 (0%)		0/6 (0%)		0/3 (0%)
Palmar-plantar erythrodysaesthesia syndrome	0/3 (0%)		0/3 (0%)		1/6 (16.7%)		0/3 (0%)
Petechiae	0/3 (0%)		0/3 (0%)		1/6 (16.7%)		0/3 (0%)
Pruritus	0/3 (0%)		0/3 (0%)		1/6 (16.7%)		0/3 (0%)
Rash	1/3 (33.3%)		0/3 (0%)		1/6 (16.7%)		0/3 (0%)
Rash maculo-papular	0/3 (0%)		0/3 (0%)		0/6 (0%)		1/3 (33.3%)
Skin hyperpigmentation	0/3 (0%)		1/3 (33.3%)		0/6 (0%)		0/3 (0%)
Skin lesion	1/3 (33.3%)		0/3 (0%)		0/6 (0%)		0/3 (0%)
Skin ulcer	0/3 (0%)		0/3 (0%)		1/6 (16.7%)		0/3 (0%)
Vascular disorders
Deep vein thrombosis	1/3 (33.3%)		0/3 (0%)		0/6 (0%)		0/3 (0%)
Hot flush	2/3 (66.7%)		0/3 (0%)		1/6 (16.7%)		0/3 (0%)

Limitations/Caveats

The study was discontinued during dose escalation in Part A, based on business related reasons as decided by the Sponsor. Therefore, the expansion cohorts (Part B) were not conducted. Hence, we have not reported the outcome measure of Part B.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

A copy of the manuscript must be provided to the sponsor for review at least 60 days before submission for publication or presentation. If requested in writing, such publication will be withheld for up to an additional 60 days.