Trial Outcomes & Findings for Safety Study of a Helper Peptide Vaccine Plus Pembrolizumab (NCT NCT02515227)

NCT ID: NCT02515227

Last Updated: 2023-08-25

Results Overview

Number of participants with dose-limiting toxicities on treatment with combination of pembrolizumab and 6MHP.

Recruitment status

COMPLETED

Study phase

PHASE1/PHASE2

Target enrollment

22 participants

Primary outcome timeframe

30 days after the last administration of study drug.

Results posted on

2023-08-25

Participant Flow

Participants were all enrolled at the University of Virginia Cancer Center and were treated as outpatients. The study opened to enrollment 11/19/2015. The first participant was enrolled 10/6/2016. The first participant's first treatment was 10/10/2016. The last participant was enrolled 6/26/2019.

Participant milestones

Participant milestones
Measure	6MHP + Pembrolizumab (PD-1 Antibody-naive Cohort) Participants who had not previously received a PD-1 or PD-L1 antibody were eligible for this cohort. They received 6MHP vaccine (200 mcg each peptide) emulsified in Montanide ISA-51 adjuvant and administered intradermally and subcutaneously on days 1, 8, 15, 43, 64, and 85. Pembrolizumab (200 mg) was administered intravenously every 3 weeks for up to 2 years, beginning on day 1. 6MHP: 6 melanoma helper vaccine comprised of 6 class II MHC-restricted helper peptides Pembrolizumab: Humanized monoclonal antibody (mAb) specific for PD-1.	6MHP + Pembrolizumab (PD-1 Antibody-experienced Cohort) Participants who had previously received a PD-1 or PD-L1 antibody were eligible for this cohort. They received 6MHP vaccine (200 mcg each peptide) emulsified in Montanide ISA-51 adjuvant and administered intradermally and subcutaneously on days 1, 8, 15, 43, 64, and 85. Pembrolizumab (200 mg) was administered intravenously every 3 weeks for up to 2 years, beginning on day 1. 6MHP: 6 melanoma helper vaccine comprised of 6 class II MHC-restricted helper peptides Pembrolizumab: Humanized monoclonal antibody (mAb) specific for PD-1.
Overall Study STARTED	6	16
Overall Study Received at Least 1 Vaccine	6	16
Overall Study COMPLETED	4	5
Overall Study NOT COMPLETED	2	11

Reasons for withdrawal

Reasons for withdrawal
Measure	6MHP + Pembrolizumab (PD-1 Antibody-naive Cohort) Participants who had not previously received a PD-1 or PD-L1 antibody were eligible for this cohort. They received 6MHP vaccine (200 mcg each peptide) emulsified in Montanide ISA-51 adjuvant and administered intradermally and subcutaneously on days 1, 8, 15, 43, 64, and 85. Pembrolizumab (200 mg) was administered intravenously every 3 weeks for up to 2 years, beginning on day 1. 6MHP: 6 melanoma helper vaccine comprised of 6 class II MHC-restricted helper peptides Pembrolizumab: Humanized monoclonal antibody (mAb) specific for PD-1.	6MHP + Pembrolizumab (PD-1 Antibody-experienced Cohort) Participants who had previously received a PD-1 or PD-L1 antibody were eligible for this cohort. They received 6MHP vaccine (200 mcg each peptide) emulsified in Montanide ISA-51 adjuvant and administered intradermally and subcutaneously on days 1, 8, 15, 43, 64, and 85. Pembrolizumab (200 mg) was administered intravenously every 3 weeks for up to 2 years, beginning on day 1. 6MHP: 6 melanoma helper vaccine comprised of 6 class II MHC-restricted helper peptides Pembrolizumab: Humanized monoclonal antibody (mAb) specific for PD-1.
Overall Study Adverse Event	0	2
Overall Study Progressive disease	2	9

Baseline Characteristics

Safety Study of a Helper Peptide Vaccine Plus Pembrolizumab

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	6MHP + Pembrolizumab (PD-1 Antibody-naive Cohort) n=6 Participants Participants who had not previously received a PD-1 or PD-L1 antibody were eligible for this cohort. They received 6MHP vaccine (200 mcg each peptide) emulsified in Montanide ISA-51 adjuvant and administered intradermally and subcutaneously on days 1, 8, 15, 43, 64, and 85. Pembrolizumab (200 mg) was administered intravenously every 3 weeks for up to 2 years, beginning on day 1. 6MHP: 6 melanoma helper vaccine comprised of 6 class II MHC-restricted helper peptides Pembrolizumab: Humanized monoclonal antibody (mAb) specific for PD-1.	6MHP + Pembrolizumab (PD-1 Antibody-experienced Cohort) n=16 Participants Participants who had previously received a PD-1 or PD-L1 antibody were eligible for this cohort. They received 6MHP vaccine (200 mcg each peptide) emulsified in Montanide ISA-51 adjuvant and administered intradermally and subcutaneously on days 1, 8, 15, 43, 64, and 85. Pembrolizumab (200 mg) was administered intravenously every 3 weeks for up to 2 years, beginning on day 1. 6MHP: 6 melanoma helper vaccine comprised of 6 class II MHC-restricted helper peptides Pembrolizumab: Humanized monoclonal antibody (mAb) specific for PD-1.	Total n=22 Participants Total of all reporting groups
Age, Customized Age at enrollment	71.5 years n=5 Participants	62.5 years n=7 Participants	63 years n=5 Participants
Sex: Female, Male Female	1 Participants n=5 Participants	8 Participants n=7 Participants	9 Participants n=5 Participants
Sex: Female, Male Male	5 Participants n=5 Participants	8 Participants n=7 Participants	13 Participants n=5 Participants
Race/Ethnicity, Customized Race at Enrollment · Caucasian/White: non-Hispanic	6 Participants n=5 Participants	15 Participants n=7 Participants	21 Participants n=5 Participants
Race/Ethnicity, Customized Race at Enrollment · African-American/Black: non-Hispanic	0 Participants n=5 Participants	1 Participants n=7 Participants	1 Participants n=5 Participants
Region of Enrollment United States	6 participants n=5 Participants	16 participants n=7 Participants	22 participants n=5 Participants
ECOG Performance Status 0	4 Participants n=5 Participants	9 Participants n=7 Participants	13 Participants n=5 Participants
ECOG Performance Status 1	2 Participants n=5 Participants	7 Participants n=7 Participants	9 Participants n=5 Participants

PRIMARY outcome

Timeframe: 30 days after the last administration of study drug.

Population: DLT was defined as unexpected adverse event (AE) at least possibly related to treatment, and, for 6MHP, grade ≥3 hematological or non-hematological toxicity, except that vaccine site ulcers were considered DLTs if ulcer \>2cm, required antibiotics or debridement; and for pembrolizumab, required permanent discontinuation per specified guidelines. Also considered DLTs were selected grade ≥2 ocular AEs, and AEs that led to stopping treatment even if they did not meet prespecified DLT criteria.

Number of participants with dose-limiting toxicities on treatment with combination of pembrolizumab and 6MHP.

Outcome measures

Outcome measures
Measure	6MHP + Pembrolizumab (PD-1 Antibody-naive Cohort) n=6 Participants Participants who had not previously received a PD-1 or PD-L1 antibody were eligible for this cohort. They received 6MHP vaccine (200 mcg each peptide) emulsified in Montanide ISA-51 adjuvant and administered intradermally and subcutaneously on days 1, 8, 15, 43, 64, and 85. Pembrolizumab (200 mg) was administered intravenously every 3 weeks for up to 2 years, beginning on day 1. 6MHP: 6 melanoma helper vaccine comprised of 6 class II MHC-restricted helper peptides Pembrolizumab: Humanized monoclonal antibody (mAb) specific for PD-1.	6MHP + Pembrolizumab (PD-1 Antibody-experienced Cohort) n=16 Participants Participants who had previously received a PD-1 or PD-L1 antibody were eligible for this cohort. They received 6MHP vaccine (200 mcg each peptide) emulsified in Montanide ISA-51 adjuvant and administered intradermally and subcutaneously on days 1, 8, 15, 43, 64, and 85. Pembrolizumab (200 mg) was administered intravenously every 3 weeks for up to 2 years, beginning on day 1. 6MHP: 6 melanoma helper vaccine comprised of 6 class II MHC-restricted helper peptides Pembrolizumab: Humanized monoclonal antibody (mAb) specific for PD-1.
Number of Participants With Dose-limiting Toxicities.	0 Participants	3 Participants

PRIMARY outcome

Timeframe: through week 104

Circulating CD4+ T cell responses to 6MHP peptides were assessed using IFN-γ ELISpot assays directly ex vivo for peripheral blood mononuclear cells (PBMC) and sentinel immunized node (SIN) lymphocytes. For each sample, the following definitions applied: Nvax=number of T cells responding to vaccine peptide; Nneg=number of T cells responding to maximum negative control; Rvax=Nvax/Nneg. For PBMC, a participant was considered to have a T-cell response (Rsp) if all the following were true: (1) Nvax exceeded Nneg by ≥ 20/100,000 CD4+ cells (0.02%), (2) (Nvax-1 SD)≥(Nneg+1 SD), (3) Rvax ≥2×, and (4) Rvax postvaccine ≥2x Rvax prevaccine. Criteria for CD4+ Rsp in a SIN included criterion (1-3). A high durable T cell response (hdRsp) required a 5× increase above baseline in any two or more time points (through day 85), and a durable immune response (dRsp) required only a 2× increase over background. A response in either PBMC or in SIN is considered a response for this endpoint.

Outcome measures

Outcome measures
Measure	6MHP + Pembrolizumab (PD-1 Antibody-naive Cohort) n=6 Participants Participants who had not previously received a PD-1 or PD-L1 antibody were eligible for this cohort. They received 6MHP vaccine (200 mcg each peptide) emulsified in Montanide ISA-51 adjuvant and administered intradermally and subcutaneously on days 1, 8, 15, 43, 64, and 85. Pembrolizumab (200 mg) was administered intravenously every 3 weeks for up to 2 years, beginning on day 1. 6MHP: 6 melanoma helper vaccine comprised of 6 class II MHC-restricted helper peptides Pembrolizumab: Humanized monoclonal antibody (mAb) specific for PD-1.	6MHP + Pembrolizumab (PD-1 Antibody-experienced Cohort) n=16 Participants Participants who had previously received a PD-1 or PD-L1 antibody were eligible for this cohort. They received 6MHP vaccine (200 mcg each peptide) emulsified in Montanide ISA-51 adjuvant and administered intradermally and subcutaneously on days 1, 8, 15, 43, 64, and 85. Pembrolizumab (200 mg) was administered intravenously every 3 weeks for up to 2 years, beginning on day 1. 6MHP: 6 melanoma helper vaccine comprised of 6 class II MHC-restricted helper peptides Pembrolizumab: Humanized monoclonal antibody (mAb) specific for PD-1.
CD4+ T Cell Responses Detected in the Peripheral Blood or Vaccine-draining Lymph Node (Sentinel Immunized Node). CD4 T cell response (Rsp) · T cell response	4 Participants	2 Participants
CD4+ T Cell Responses Detected in the Peripheral Blood or Vaccine-draining Lymph Node (Sentinel Immunized Node). CD4 T cell response (Rsp) · No T cell response	2 Participants	14 Participants
CD4+ T Cell Responses Detected in the Peripheral Blood or Vaccine-draining Lymph Node (Sentinel Immunized Node). CD4 high durable T cell response (hdRsp) · T cell response	1 Participants	0 Participants
CD4+ T Cell Responses Detected in the Peripheral Blood or Vaccine-draining Lymph Node (Sentinel Immunized Node). CD4 high durable T cell response (hdRsp) · No T cell response	5 Participants	16 Participants
CD4+ T Cell Responses Detected in the Peripheral Blood or Vaccine-draining Lymph Node (Sentinel Immunized Node). CD4 durable T cell response (dRsp) · T cell response	1 Participants	1 Participants
CD4+ T Cell Responses Detected in the Peripheral Blood or Vaccine-draining Lymph Node (Sentinel Immunized Node). CD4 durable T cell response (dRsp) · No T cell response	5 Participants	15 Participants

SECONDARY outcome

Timeframe: up to day 22

Evaluation of tumor infiltration by T cells.Tumor biopsies were obtained pretreatment and day 22 for 12 participants and were evaluated with multiplex immunofluorescence histology (mIFH). CD8+ T cell data were evaluated. CD4+ T cells were not reported because of technical challenges with that antibody. These 12 participants with evaluable tumor samples included 3 on the PD-1 antibody-naive cohort, and 9 on the antibody-experienced cohort.

Outcome measures

Outcome measures
Measure	6MHP + Pembrolizumab (PD-1 Antibody-naive Cohort) n=3 Participants Participants who had not previously received a PD-1 or PD-L1 antibody were eligible for this cohort. They received 6MHP vaccine (200 mcg each peptide) emulsified in Montanide ISA-51 adjuvant and administered intradermally and subcutaneously on days 1, 8, 15, 43, 64, and 85. Pembrolizumab (200 mg) was administered intravenously every 3 weeks for up to 2 years, beginning on day 1. 6MHP: 6 melanoma helper vaccine comprised of 6 class II MHC-restricted helper peptides Pembrolizumab: Humanized monoclonal antibody (mAb) specific for PD-1.	6MHP + Pembrolizumab (PD-1 Antibody-experienced Cohort) n=9 Participants Participants who had previously received a PD-1 or PD-L1 antibody were eligible for this cohort. They received 6MHP vaccine (200 mcg each peptide) emulsified in Montanide ISA-51 adjuvant and administered intradermally and subcutaneously on days 1, 8, 15, 43, 64, and 85. Pembrolizumab (200 mg) was administered intravenously every 3 weeks for up to 2 years, beginning on day 1. 6MHP: 6 melanoma helper vaccine comprised of 6 class II MHC-restricted helper peptides Pembrolizumab: Humanized monoclonal antibody (mAb) specific for PD-1.
Number of T Cells in the Tumor Microenvironment CD8 T cells per mm^2 in day 0 tumor	28.7 cells per mm^2 tumor Interval 16.7 to 324.9	125.5 cells per mm^2 tumor Interval 18.9 to 267.1
Number of T Cells in the Tumor Microenvironment CD8+ T cells per mm^2 in day 22 tumor	259.1 cells per mm^2 tumor Interval 179.6 to 396.33	164.7 cells per mm^2 tumor Interval 63.1 to 585.4

SECONDARY outcome

Timeframe: up to day 22

Population: Immune signature data have not been collected from the tumor microenvironment.

Evaluation of cytokine profile for CD4+ T cells in tumor microenvironment. Data for this outcome have not been collected due to completion of funding for this study.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: up to week 104

Population: Due to completion of funding for this study, data have not been collected to assess epitope-spreading through the measurement of the induction of CD8+ T cell responses to defined melanoma antigens.

Evaluation of epitope-spreading through the measurement of the induction of CD8+ T cell responses to defined melanoma antigens.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: up to week 104

Population: Antibody responses to 6MHP have not been measured, due to completion of funding for this trial.

Evaluation of antibody responses to 6MHP

Outcome measures

Outcome data not reported

Adverse Events

6MHP + Pembrolizumab (PD-1 Antibody-naive Cohort)

Serious events: 0 serious events

Other events: 6 other events

Deaths: 0 deaths

6MHP + Pembrolizumab (PD-1 Antibody-experienced Cohort)

Serious events: 0 serious events

Other events: 16 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Additional Information

Craig Slingluff, MD

University of Virginia

Phone: 434 924-9311

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Measure	6MHP + Pembrolizumab (PD-1 Antibody-naive Cohort) n=6 participants at risk Participants who had not previously received a PD-1 or PD-L1 antibody were eligible for this cohort. They received 6MHP vaccine (200 mcg each peptide) emulsified in Montanide ISA-51 adjuvant and administered intradermally and subcutaneously on days 1, 8, 15, 43, 64, and 85. Pembrolizumab (200 mg) was administered intravenously every 3 weeks for up to 2 years, beginning on day 1. 6MHP: 6 melanoma helper vaccine comprised of 6 class II MHC-restricted helper peptides Pembrolizumab: Humanized monoclonal antibody (mAb) specific for PD-1.	6MHP + Pembrolizumab (PD-1 Antibody-experienced Cohort) n=16 participants at risk Participants who had previously received a PD-1 or PD-L1 antibody were eligible for this cohort. They received 6MHP vaccine (200 mcg each peptide) emulsified in Montanide ISA-51 adjuvant and administered intradermally and subcutaneously on days 1, 8, 15, 43, 64, and 85. Pembrolizumab (200 mg) was administered intravenously every 3 weeks for up to 2 years, beginning on day 1. 6MHP: 6 melanoma helper vaccine comprised of 6 class II MHC-restricted helper peptides Pembrolizumab: Humanized monoclonal antibody (mAb) specific for PD-1.
General disorders Fatigue	66.7% 4/6 • Adverse events and dose-limiting toxicities (DLTs) were monitored up to 30 days after the last study treatment.	87.5% 14/16 • Adverse events and dose-limiting toxicities (DLTs) were monitored up to 30 days after the last study treatment.
Blood and lymphatic system disorders Anemia	16.7% 1/6 • Adverse events and dose-limiting toxicities (DLTs) were monitored up to 30 days after the last study treatment.	50.0% 8/16 • Adverse events and dose-limiting toxicities (DLTs) were monitored up to 30 days after the last study treatment.
Endocrine disorders Adrenal Insufficiency	0.00% 0/6 • Adverse events and dose-limiting toxicities (DLTs) were monitored up to 30 days after the last study treatment.	12.5% 2/16 • Adverse events and dose-limiting toxicities (DLTs) were monitored up to 30 days after the last study treatment.
Gastrointestinal disorders Abdominal Pain	0.00% 0/6 • Adverse events and dose-limiting toxicities (DLTs) were monitored up to 30 days after the last study treatment.	12.5% 2/16 • Adverse events and dose-limiting toxicities (DLTs) were monitored up to 30 days after the last study treatment.
Gastrointestinal disorders Diarrhea	16.7% 1/6 • Adverse events and dose-limiting toxicities (DLTs) were monitored up to 30 days after the last study treatment.	6.2% 1/16 • Adverse events and dose-limiting toxicities (DLTs) were monitored up to 30 days after the last study treatment.
Gastrointestinal disorders Dyspepsia	0.00% 0/6 • Adverse events and dose-limiting toxicities (DLTs) were monitored up to 30 days after the last study treatment.	18.8% 3/16 • Adverse events and dose-limiting toxicities (DLTs) were monitored up to 30 days after the last study treatment.
Gastrointestinal disorders Nausea	0.00% 0/6 • Adverse events and dose-limiting toxicities (DLTs) were monitored up to 30 days after the last study treatment.	31.2% 5/16 • Adverse events and dose-limiting toxicities (DLTs) were monitored up to 30 days after the last study treatment.
General disorders Chills	16.7% 1/6 • Adverse events and dose-limiting toxicities (DLTs) were monitored up to 30 days after the last study treatment.	12.5% 2/16 • Adverse events and dose-limiting toxicities (DLTs) were monitored up to 30 days after the last study treatment.
General disorders Fever	50.0% 3/6 • Adverse events and dose-limiting toxicities (DLTs) were monitored up to 30 days after the last study treatment.	18.8% 3/16 • Adverse events and dose-limiting toxicities (DLTs) were monitored up to 30 days after the last study treatment.
General disorders Flu-like symptoms	16.7% 1/6 • Adverse events and dose-limiting toxicities (DLTs) were monitored up to 30 days after the last study treatment.	6.2% 1/16 • Adverse events and dose-limiting toxicities (DLTs) were monitored up to 30 days after the last study treatment.
General disorders Injection site reaction	100.0% 6/6 • Adverse events and dose-limiting toxicities (DLTs) were monitored up to 30 days after the last study treatment.	87.5% 14/16 • Adverse events and dose-limiting toxicities (DLTs) were monitored up to 30 days after the last study treatment.
General disorders Pain	0.00% 0/6 • Adverse events and dose-limiting toxicities (DLTs) were monitored up to 30 days after the last study treatment.	12.5% 2/16 • Adverse events and dose-limiting toxicities (DLTs) were monitored up to 30 days after the last study treatment.
Injury, poisoning and procedural complications Bruising	33.3% 2/6 • Adverse events and dose-limiting toxicities (DLTs) were monitored up to 30 days after the last study treatment.	18.8% 3/16 • Adverse events and dose-limiting toxicities (DLTs) were monitored up to 30 days after the last study treatment.
Investigations Alanine Aminotransferase increased	0.00% 0/6 • Adverse events and dose-limiting toxicities (DLTs) were monitored up to 30 days after the last study treatment.	12.5% 2/16 • Adverse events and dose-limiting toxicities (DLTs) were monitored up to 30 days after the last study treatment.
Investigations Alkaline phosphatase increased	0.00% 0/6 • Adverse events and dose-limiting toxicities (DLTs) were monitored up to 30 days after the last study treatment.	12.5% 2/16 • Adverse events and dose-limiting toxicities (DLTs) were monitored up to 30 days after the last study treatment.
Investigations Aspartate aminotransferase increased	16.7% 1/6 • Adverse events and dose-limiting toxicities (DLTs) were monitored up to 30 days after the last study treatment.	31.2% 5/16 • Adverse events and dose-limiting toxicities (DLTs) were monitored up to 30 days after the last study treatment.
Investigations Creatinine increased	0.00% 0/6 • Adverse events and dose-limiting toxicities (DLTs) were monitored up to 30 days after the last study treatment.	12.5% 2/16 • Adverse events and dose-limiting toxicities (DLTs) were monitored up to 30 days after the last study treatment.
Investigations Lymphocyte count decreased	33.3% 2/6 • Adverse events and dose-limiting toxicities (DLTs) were monitored up to 30 days after the last study treatment.	25.0% 4/16 • Adverse events and dose-limiting toxicities (DLTs) were monitored up to 30 days after the last study treatment.
Metabolism and nutrition disorders Anorexia	0.00% 0/6 • Adverse events and dose-limiting toxicities (DLTs) were monitored up to 30 days after the last study treatment.	25.0% 4/16 • Adverse events and dose-limiting toxicities (DLTs) were monitored up to 30 days after the last study treatment.
Metabolism and nutrition disorders Dehydration	0.00% 0/6 • Adverse events and dose-limiting toxicities (DLTs) were monitored up to 30 days after the last study treatment.	12.5% 2/16 • Adverse events and dose-limiting toxicities (DLTs) were monitored up to 30 days after the last study treatment.
Metabolism and nutrition disorders Hyperuricemia	16.7% 1/6 • Adverse events and dose-limiting toxicities (DLTs) were monitored up to 30 days after the last study treatment.	6.2% 1/16 • Adverse events and dose-limiting toxicities (DLTs) were monitored up to 30 days after the last study treatment.
Metabolism and nutrition disorders Hyponatremia	0.00% 0/6 • Adverse events and dose-limiting toxicities (DLTs) were monitored up to 30 days after the last study treatment.	12.5% 2/16 • Adverse events and dose-limiting toxicities (DLTs) were monitored up to 30 days after the last study treatment.
Musculoskeletal and connective tissue disorders Arthralgia	33.3% 2/6 • Adverse events and dose-limiting toxicities (DLTs) were monitored up to 30 days after the last study treatment.	18.8% 3/16 • Adverse events and dose-limiting toxicities (DLTs) were monitored up to 30 days after the last study treatment.
Metabolism and nutrition disorders Myalgia	33.3% 2/6 • Adverse events and dose-limiting toxicities (DLTs) were monitored up to 30 days after the last study treatment.	12.5% 2/16 • Adverse events and dose-limiting toxicities (DLTs) were monitored up to 30 days after the last study treatment.
Nervous system disorders Headache	16.7% 1/6 • Adverse events and dose-limiting toxicities (DLTs) were monitored up to 30 days after the last study treatment.	18.8% 3/16 • Adverse events and dose-limiting toxicities (DLTs) were monitored up to 30 days after the last study treatment.
Respiratory, thoracic and mediastinal disorders Allergic rhinitis	16.7% 1/6 • Adverse events and dose-limiting toxicities (DLTs) were monitored up to 30 days after the last study treatment.	6.2% 1/16 • Adverse events and dose-limiting toxicities (DLTs) were monitored up to 30 days after the last study treatment.
Respiratory, thoracic and mediastinal disorders Dyspnea	16.7% 1/6 • Adverse events and dose-limiting toxicities (DLTs) were monitored up to 30 days after the last study treatment.	6.2% 1/16 • Adverse events and dose-limiting toxicities (DLTs) were monitored up to 30 days after the last study treatment.
Skin and subcutaneous tissue disorders Hyperhidrosis	0.00% 0/6 • Adverse events and dose-limiting toxicities (DLTs) were monitored up to 30 days after the last study treatment.	25.0% 4/16 • Adverse events and dose-limiting toxicities (DLTs) were monitored up to 30 days after the last study treatment.
Skin and subcutaneous tissue disorders Pruritis	50.0% 3/6 • Adverse events and dose-limiting toxicities (DLTs) were monitored up to 30 days after the last study treatment.	18.8% 3/16 • Adverse events and dose-limiting toxicities (DLTs) were monitored up to 30 days after the last study treatment.
Skin and subcutaneous tissue disorders Rash maculo-papular	50.0% 3/6 • Adverse events and dose-limiting toxicities (DLTs) were monitored up to 30 days after the last study treatment.	18.8% 3/16 • Adverse events and dose-limiting toxicities (DLTs) were monitored up to 30 days after the last study treatment.
Skin and subcutaneous tissue disorders Skin induration	83.3% 5/6 • Adverse events and dose-limiting toxicities (DLTs) were monitored up to 30 days after the last study treatment.	68.8% 11/16 • Adverse events and dose-limiting toxicities (DLTs) were monitored up to 30 days after the last study treatment.
Skin and subcutaneous tissue disorders Skin ulceration	0.00% 0/6 • Adverse events and dose-limiting toxicities (DLTs) were monitored up to 30 days after the last study treatment.	12.5% 2/16 • Adverse events and dose-limiting toxicities (DLTs) were monitored up to 30 days after the last study treatment.
Vascular disorders Hypotension	0.00% 0/6 • Adverse events and dose-limiting toxicities (DLTs) were monitored up to 30 days after the last study treatment.	12.5% 2/16 • Adverse events and dose-limiting toxicities (DLTs) were monitored up to 30 days after the last study treatment.