Pembrolizumab and Doxorubicin Hydrochloride in Treating Patients With Sarcoma That is Metastatic or Cannot Be Removed by Surgery

• Sponsor: Fred Hutchinson Cancer Center (Other)
• Overall Status: Completed
• CT.gov ID: NCT02888665
• Collaborator: National Cancer Institute (NCI) (NIH)
• Enrollment: 37
• Location: 1
• Arm: 1
• Actual Duration (Months): 46.1
• Patients Per Site Per Month: 0.8

Study Details

Study Description

Brief Summary

This phase I/II trial studies the side effects and best dose of doxorubicin hydrochloride when given together with pembrolizumab and to see how well they work in treating patients with sarcoma that have spread to other parts of the body or that cannot be removed by surgery. Drugs used in chemotherapy, such as doxorubicin hydrochloride, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving doxorubicin hydrochloride together with pembrolizumab may work better in treating patients with sarcoma.

Condition or Disease	Intervention/Treatment	Phase
Sarcoma	Drug: Doxorubicin Hydrochloride; Other: Laboratory Biomarker Analysis; Biological: Pembrolizumab	Phase 1/Phase 2

Detailed Description

PRIMARY OBJECTIVES:

1. To assess the safety and tolerability of the combination of pembrolizumab and doxorubicin hydrochloride (doxorubicin) in patients with advanced soft tissue sarcoma (STS).

2. To assess the clinical response rate of advanced soft tissue sarcoma (STS) patients receiving the combination of pembrolizumab and doxorubicin.

SECONDARY OBJECTIVES:

1. To explore the clinical activity of pembrolizumab in subjects with advanced STS with respect to time to response.

2. To explore the clinical activity of pembrolizumab in subjects with advanced STS with respect to duration of response.

3. To explore the clinical activity of pembrolizumab in subjects with advanced STS with respect to progression-free survival (PFS).

4. To explore the clinical activity of pembrolizumab in subjects with advanced STS with respect to overall survival.

TERTIARY OBJECTIVES:

1. To compare response rates between patients with high levels of PD-L1 expression with those who have PD-L1 absent.

OUTLINE: This is a phase I, dose-escalation study of doxorubicin hydrochloride followed by a phase II study.

Patients receive pembrolizumab intravenously (IV) over 30 minutes on day 1 and doxorubicin hydrochloride IV over 1-3 hours on day 1 of courses 2-7 only. Treatment repeats every 21 days for up to 35 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days and then every 12 weeks.

Study Design

• Study Type: Interventional
• Actual Enrollment: 37 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Trial of Pembrolizumab in Combination With Doxorubicin as Treatment for Patients With Advanced Sarcomas
• Actual Study Start Date: Dec 5, 2016
• Actual Primary Completion Date: Mar 17, 2020
• Actual Study Completion Date: Oct 9, 2020

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Treatment (pembrolizumab, doxorubicin hydrochloride) Patients receive pembrolizumab IV over 30 minutes on day 1 and doxorubicin hydrochloride IV over 1-3 hours on day 1 of courses 2-7 only. Treatment repeats every 21 days for up to 35 courses in the absence of disease progression or unacceptable toxicity.

Drug: Doxorubicin Hydrochloride; Given IV; Other Names: 5,12-Naphthacenedione, 10-[(3-amino-2,3,6-trideoxy-alpha-L-lyxo-hexopyranosyl)oxy]-7,8, 9,10-tetrahydro-6,8,11-trihydroxy-8-(hydroxyacetyl)-1-methoxy-, hydrochloride, (8S-cis)- (9CI) ADM Adriacin Adriamycin Adriamycin Hydrochloride Adriamycin PFS Adriamycin RDF ADRIAMYCIN, HYDROCHLORIDE Adriamycine Adriblastina Adriblastine Adrimedac Chloridrato de Doxorrubicina DOX DOXO-CELL Doxolem Doxorubicin.HCl Doxorubin Farmiblastina FI 106 FI-106 hydroxydaunorubicin Rubex ; Other: Laboratory Biomarker Analysis; Correlative studies; Biological: Pembrolizumab; Given IV; Other Names: Keytruda Lambrolizumab MK-3475 SCH 900475

Outcome Measures

Primary Outcome Measures

1. Maximum Tolerated Dose (MTD) of Doxorubicin Hydrochloride Plus Pembrolizumab According to the National Cancer Institute (NCI) Common Terminology for Adverse Events (CTCAE) Version 4.0 (Phase I) [Up to 42 days (6 weeks)]

   Defined as a dose limiting toxicity (DLT) in less than 2 of 6 subjects. Only Phase 1 subjects will be evaluated for MTD.

2. Objective Response Rate (ORR) (Phase II) [Up to 2 years]

   Evaluated per Response Evaluation Criteria in Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by CT. Complete Response (CR) is a complete elimination of the tumor; Partial Response (PR) is 30% reduction. If a subject experienced a PR, this was required to be confirmed with a second scan at the next appropriate cycle.

Secondary Outcome Measures

1. Duration of Response [Up to 2 years]

   Duration of response is the mean time to progression for all subjects who responded.

2. Median Progression-free Survival (PFS) [Up to 2 years]

   The Kaplan-Meier method will be used to estimate median PFS.

3. Overall Survival (OS) [Up to 2 years]

   The Kaplan-Meier method will be used to estimate median OS.

4. Time to Response [Up to 2 years]

   Average time to response

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Be willing and able to provide written informed consent/assent for the trial

• Have measurable disease based on Response Evaluation Criteria in Solid Tumors (RECIST) 1.1

• Have metastatic or unresectable sarcoma

• Have a performance status of 0 to 1 on the Eastern Cooperative Oncology Group (ECOG) performance scale

• Absolute neutrophil count (ANC) >= 1,500/mcL (within 10 days of treatment initiation)

• Platelets >= 100,000/mcL (within 10 days of treatment initiation)

• Hemoglobin >= 9 g/dL (within 10 days of treatment initiation) or >= 5.6 mmol/L without transfusion or erythropoietin (EPO) dependency (within 7 days of assessment)

• Serum creatinine =< 1.5 X upper limit of normal (ULN) OR measured or calculated creatinine clearance (glomerular filtration rate [GFR] can also be used in place of creatinine or creatinine clearance [CrCl]) >= 60 mL/min for subject with creatinine levels > 1.5 X institutional ULN (within 10 days of treatment initiation)

• Serum total bilirubin =< 1.5 X ULN OR direct bilirubin =< ULN for subjects with total bilirubin levels > 1.5 ULN (within 10 days of treatment initiation)

• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 X ULN OR =< 5 X ULN for subjects with liver metastases (within 10 days of treatment initiation)

• Albumin >= 2.5 mg/dL (within 10 days of treatment initiation)

• International normalized ratio (INR) or prothrombin time (PT) =< 1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or partial thromboplastin time (PTT) is within therapeutic range of intended use of anticoagulants (within 10 days of treatment initiation)

• Activated partial thromboplastin time (aPTT) =< 1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants (within 10 days of treatment initiation)

• Female subject of childbearing potential should have a negative urine or serum pregnancy within 72 hours prior to receiving the first dose of study medication; if the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required

• Female subjects of childbearing potential should be willing to use 2 methods of birth control or be surgically sterile, or abstain from heterosexual activity for the course of the study through 120 days after the last dose of study medication; subjects of childbearing potential are those who have not been surgically sterilized or have not been free from menses for > 1 year

• Male subjects should agree to use an adequate method of contraception starting with the first dose of study therapy through 120 days after the last dose of study therapy

• Ejection fraction > 45% by either multi-gated acquisition scan (MUGA) scan or echocardiogram

Exclusion Criteria:

• Has prior treatment using an anthracycline

• Has one of the following sarcoma subtypes where combining anthracyclines with other chemotherapies is established as the standard of care: osteosarcoma, Ewings sarcoma, embryonal rhabdomyosarcoma, alveolar rhabdomyosarcoma

• Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks of the first dose of treatment

• Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment

• Has a known history of active TB (bacillus tuberculosis)

• Hypersensitivity to pembrolizumab or any of its excipients

• Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study day 1 or who has not recovered (i.e., =< grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier

• Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to study day 1 or who has not recovered (i.e., =< grade 1 or at baseline) from adverse events due to a previously administered agent

• Note: Subjects with =< grade 2 neuropathy are an exception to this criterion and may qualify for the study

• Note: If subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy

• Has a known additional malignancy that is progressing or requires active treatment; exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer

• Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis; subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment; this exception does not include carcinomatous meningitis which is excluded regardless of clinical stability

• Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs); replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment

• Has known history of, or any evidence of active, non-infectious pneumonitis

• Has an active infection requiring systemic therapy

• Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator

• Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial

• Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of trial treatment

• Has received prior therapy with an anti-programed death receptor 1 (PD-1), anti-PD-L1, anti-program death receptor ligand 2 (PD-L2) agent or anti-CTLA4

• Has a known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies)

• Has known active hepatitis B (e.g., hepatitis B surface antigen [HBsAg] reactive) or hepatitis C (e.g., hepatitis C virus [HCV] ribonucleic acid [RNA] [qualitative] is detected)

• Has received a live vaccine within 30 days of planned start of study therapy

• Note: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist) are live attenuated vaccines, and are not allowed

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Fred Hutch/University of Washington Cancer Consortium	Seattle	Washington	United States	98109

Sponsors and Collaborators

• Fred Hutchinson Cancer Center
• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Seth Pollack, Fred Hutch/University of Washington Cancer Consortium

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Oct 4, 2018
• Informed Consent Form - Apr 30, 2020

More Information

Publications

None provided.

• Responsible Party: Seth Pollack, Steven T. Rosen, MD, Professor of Cancer Biology, Northwestern University
• ClinicalTrials.gov Identifier: NCT02888665
• Other Study ID Numbers: 9624; NCI-2016-01286; 9624; P30CA015704; RG9216017
• First Posted: Sep 5, 2016
• Last Update Posted: May 26, 2021
• Last Verified: May 1, 2021

• Additional relevant MeSH terms: Sarcoma; Doxorubicin; Liposomal doxorubicin; Pembrolizumab

Study Results

Participant Flow

Arm/Group Title	Phase 1, Part 1	Phase 1, Part 2	Phase 2
Arm/Group Description	Subjects received 45 mg/m2 doxorubicin plus 200 mg flat dose of pembrolizumab.	Subjects received 75 mg/m2 doxorubicin + 200 mg flat dose of pembrolizumab.	Subjects received 75 mg/m2 doxorubicin + 200 mg flat dose pembrolizumab.
Period Title: Overall Study
STARTED	3	3	31
COMPLETED	3	3	31
NOT COMPLETED	0	0	0

Baseline Characteristics

Arm/Group Title	Phase 1, Part 1	Phase 1, Part 2	Phase 2	Total
Arm/Group Description	Subjects received 45 mg/m2 doxorubicin plus 200 mg flat dose of pembrolizumab.	Subjects received 75 mg/m2 doxorubicin + 200 mg flat dose of pembrolizumab.	Subjects received 75 mg/m2 doxorubicin + 200 mg flat dose pembrolizumab.	Total of all reporting groups
Overall Participants	3	3	31	37
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	0 0%
Between 18 and 65 years	2 66.7%	2 66.7%	23 74.2%	27 73%
>=65 years	1 33.3%	1 33.3%	8 25.8%	10 27%
Sex: Female, Male (Count of Participants)
Female	0 0%	1 33.3%	14 45.2%	15 40.5%
Male	3 100%	2 66.7%	17 54.8%	22 59.5%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%	1 33.3%	4 12.9%	5 13.5%
Not Hispanic or Latino	3 100%	2 66.7%	26 83.9%	31 83.8%
Unknown or Not Reported	0 0%	0 0%	1 3.2%	1 2.7%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	2 6.5%	2 5.4%
Asian	0 0%	0 0%	2 6.5%	2 5.4%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%
Black or African American	0 0%	0 0%	1 3.2%	1 2.7%
White	3 100%	2 66.7%	22 71%	27 73%
More than one race	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	1 33.3%	4 12.9%	5 13.5%

Outcome Measures

1. Primary Outcome

Title	Maximum Tolerated Dose (MTD) of Doxorubicin Hydrochloride Plus Pembrolizumab According to the National Cancer Institute (NCI) Common Terminology for Adverse Events (CTCAE) Version 4.0 (Phase I)
Description	Defined as a dose limiting toxicity (DLT) in less than 2 of 6 subjects. Only Phase 1 subjects will be evaluated for MTD.
Time Frame	Up to 42 days (6 weeks)

Outcome Measure Data

Analysis Population Description

Only Phase 1 subjects were evaluated for a Maximum Tolerated Dose (MTD) based off of Dose-Limiting Toxicities experienced per subject as defined in the protocol.

Arm/Group Title	Phase 1 Cohort 1	Phase 1 Cohort 2
Arm/Group Description	Subjects received 45 mg/m2 of doxorubicin plus 200 mg flat dose of pembrolizumab.	Subjects received 75 mg/m2 of doxorubicin plus 200 mg flat dose of pembrolizumab.
Measure Participants	3	3
Count of Participants [Participants]	0 0%	0 0%

2. Primary Outcome

Title	Objective Response Rate (ORR) (Phase II)
Description	Evaluated per Response Evaluation Criteria in Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by CT. Complete Response (CR) is a complete elimination of the tumor; Partial Response (PR) is 30% reduction. If a subject experienced a PR, this was required to be confirmed with a second scan at the next appropriate cycle.
Time Frame	Up to 2 years

Outcome Measure Data

Analysis Population Description

Only Phase 2 subjects were evaluated for this outcome as Phase 1 subjects were only included in the protocol for safety evaluation.

Arm/Group Title	Phase 2: Treatment (Pembrolizumab, Doxorubicin Hydrochloride)
Arm/Group Description	Patients receive pembrolizumab IV over 30 minutes on day 1 and doxorubicin hydrochloride IV over 1-3 hours on day 1 of courses 2-7 only. Treatment repeats every 21 days for up to 35 courses in the absence of disease progression or unacceptable toxicity. Doxorubicin Hydrochloride: Given IV Laboratory Biomarker Analysis: Correlative studies Pembrolizumab: Given IV
Measure Participants	31
Number [percent of participants]	13 433.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Phase 1 Cohort 1
	Comments	The primary objective of the phase II design compared ORR with historical rates (Judson et al. Lancet Onc., 2014). A 2-stage design with null hypothesis of 15% using a 1-sided 0.05 α level test has 85% power to detect an increase to 35%. This required up to 35 patients. After 2 responses in stage 1 (20 pts), the study moved to stage 2 (15 pts). If 10 responses were seen (29%), this would have ruled out an ORR of 15%. The study was closed when it became clear we would not meet this benchmark.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Other Statistical Analysis		see above. target ORR was not met.

3. Secondary Outcome

Title	Duration of Response
Description	Duration of response is the mean time to progression for all subjects who responded.
Time Frame	Up to 2 years

Outcome Measure Data

Analysis Population Description

Only 5 appropriate subjects had partial responses for evaluation.

Arm/Group Title	Treatment (Pembrolizumab, Doxorubicin Hydrochloride)
Arm/Group Description	Patients receive pembrolizumab IV over 30 minutes on day 1 and doxorubicin hydrochloride IV over 1-3 hours on day 1 of courses 2-7 only. Treatment repeats every 21 days for up to 35 courses in the absence of disease progression or unacceptable toxicity. Doxorubicin Hydrochloride: Given IV Laboratory Biomarker Analysis: Correlative studies Pembrolizumab: Given IV
Measure Participants	5
Mean (Standard Deviation) [Days]	247 (180)

4. Secondary Outcome

Title	Median Progression-free Survival (PFS)
Description	The Kaplan-Meier method will be used to estimate median PFS.
Time Frame	Up to 2 years

Outcome Measure Data

Analysis Population Description

This combined the phase I and phase II populations as we had intended for this analysis.

Arm/Group Title	Treatment (Pembrolizumab, Doxorubicin Hydrochloride)
Arm/Group Description	Patients receive pembrolizumab IV over 30 minutes on day 1 and doxorubicin hydrochloride IV over 1-3 hours on day 1 of courses 2-7 only. Treatment repeats every 21 days for up to 35 courses in the absence of disease progression or unacceptable toxicity. Doxorubicin Hydrochloride: Given IV Laboratory Biomarker Analysis: Correlative studies Pembrolizumab: Given IV
Measure Participants	37
Median (95% Confidence Interval) [months]	8.1

5. Secondary Outcome

Title	Overall Survival (OS)
Description	The Kaplan-Meier method will be used to estimate median OS.
Time Frame	Up to 2 years

Outcome Measure Data

Analysis Population Description

This combined the phase I and phase II populations as we had intended for this analysis.

Arm/Group Title	Treatment (Pembrolizumab, Doxorubicin Hydrochloride)
Arm/Group Description	Patients receive pembrolizumab IV over 30 minutes on day 1 and doxorubicin hydrochloride IV over 1-3 hours on day 1 of courses 2-7 only. Treatment repeats every 21 days for up to 35 courses in the absence of disease progression or unacceptable toxicity. Doxorubicin Hydrochloride: Given IV Laboratory Biomarker Analysis: Correlative studies Pembrolizumab: Given IV
Measure Participants	37
Median (95% Confidence Interval) [months]	27.6

6. Secondary Outcome

Title	Time to Response
Description	Average time to response
Time Frame	Up to 2 years

Outcome Measure Data

Analysis Population Description

Only 5 appropriate subjects had partial responses for evaluation.

Arm/Group Title	Treatment (Pembrolizumab, Doxorubicin Hydrochloride)
Arm/Group Description	Patients receive pembrolizumab IV over 30 minutes on day 1 and doxorubicin hydrochloride IV over 1-3 hours on day 1 of courses 2-7 only. Treatment repeats every 21 days for up to 35 courses in the absence of disease progression or unacceptable toxicity. Doxorubicin Hydrochloride: Given IV Laboratory Biomarker Analysis: Correlative studies Pembrolizumab: Given IV
Measure Participants	5
Mean (Standard Deviation) [Days]	152.2 (65)

Adverse Events

Time Frame	Adverse event data was collected beginning from date of consent to 30 days post discontinuation of study treatment. (Up to 2 years of therapy with 1 cycle equaling 21 days)
Arm/Group Title	Phase 1 Cohort 1		Phase 1 Cohort 2		Phase 2
Arm/Group Description	Subjects received 45 mg/m2 doxorubicin plus 200 mg flat dose of pembrolizumab.		Subjects received 75 mg/m2 doxorubicin plus 200 mg flat dose of pembrolizumab.		Subjects received 75 mg/m2 doxorubicin plus 200 mg flat dose pembrolizumab.
All Cause Mortality
	Phase 1 Cohort 1		Phase 1 Cohort 2		Phase 2
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/3 (66.7%)		0/3 (0%)		15/31 (48.4%)
Serious Adverse Events
	Phase 1 Cohort 1		Phase 1 Cohort 2		Phase 2
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/3 (33.3%)		2/3 (66.7%)		13/31 (41.9%)
Blood and lymphatic system disorders
Febrile Neutropenia	0/3 (0%)	0	0/3 (0%)	0	2/31 (6.5%)	2
Leukocytosis	1/3 (33.3%)	1	0/3 (0%)	0	0/31 (0%)	0
Tumor thrombus	1/3 (33.3%)	1	0/3 (0%)	0	0/31 (0%)	0
Cardiac disorders
Ejection fraction decreased	0/3 (0%)	0	1/3 (33.3%)	1	0/31 (0%)	0
Pulmonary infarct	1/3 (33.3%)	1	0/3 (0%)	0	0/31 (0%)	0
Heart failure	0/3 (0%)	0	1/3 (33.3%)	1	0/31 (0%)	0
Ear and labyrinth disorders
Vertigo	0/3 (0%)	0	0/3 (0%)	0	1/31 (3.2%)	1
Endocrine disorders
Hypothyroidism	0/3 (0%)	0	0/3 (0%)	0	1/31 (3.2%)	1
Adrenal insufficiency	0/3 (0%)	0	1/3 (33.3%)	2	0/31 (0%)	0
Gastrointestinal disorders
Abdominal Pain	0/3 (0%)	0	0/3 (0%)	0	3/31 (9.7%)	3
Diarrhea	0/3 (0%)	0	0/3 (0%)	0	1/31 (3.2%)	1
Constipation	0/3 (0%)	0	0/3 (0%)	0	1/31 (3.2%)	1
Partial Bowel Obstruction	0/3 (0%)	0	1/3 (33.3%)	2	0/31 (0%)	0
Mid-esophageal erythema	0/3 (0%)	0	1/3 (33.3%)	1	0/31 (0%)	0
Denuded mucosa	0/3 (0%)	0	1/3 (33.3%)	1	0/31 (0%)	0
Malignant bowel obstruction	0/3 (0%)	0	0/3 (0%)	0	1/31 (3.2%)	1
Small bowel obstruction	0/3 (0%)	0	0/3 (0%)	0	1/31 (3.2%)	1
Odynophagia	0/3 (0%)	0	0/3 (0%)	0	1/31 (3.2%)	1
Ascites	0/3 (0%)	0	0/3 (0%)	0	1/31 (3.2%)	1
Mucositis oral	0/3 (0%)	0	0/3 (0%)	0	2/31 (6.5%)	2
General disorders
Atypical Chest Pain	1/3 (33.3%)	1	0/3 (0%)	0	0/31 (0%)	0
Postprandial Chest Pain	0/3 (0%)	0	1/3 (33.3%)	1	0/31 (0%)	0
Failure to thrive	0/3 (0%)	0	0/3 (0%)	0	1/31 (3.2%)	1
Non-cardiac chest pain	0/3 (0%)	0	0/3 (0%)	0	1/31 (3.2%)	1
Fever	0/3 (0%)	0	0/3 (0%)	0	1/31 (3.2%)	1
Infections and infestations
Oropharyngeal thrush	0/3 (0%)	0	0/3 (0%)	0	1/31 (3.2%)	1
Thrush	0/3 (0%)	0	0/3 (0%)	0	1/31 (3.2%)	1
Urinary tract infection	0/3 (0%)	0	1/3 (33.3%)	1	0/31 (0%)	0
Pelvic infection	0/3 (0%)	0	1/3 (33.3%)	1	0/31 (0%)	0
Kidney Infection	0/3 (0%)	0	0/3 (0%)	0	1/31 (3.2%)	1
Lung infection	0/3 (0%)	0	0/3 (0%)	0	1/31 (3.2%)	1
Sepsis	0/3 (0%)	0	0/3 (0%)	0	1/31 (3.2%)	1
Investigations
Elevated troponin	0/3 (0%)	0	0/3 (0%)	0	1/31 (3.2%)	1
Pancytopenia	0/3 (0%)	0	0/3 (0%)	0	1/31 (3.2%)	1
Metabolism and nutrition disorders
Anorexia	0/3 (0%)	0	0/3 (0%)	0	1/31 (3.2%)	1
Dehydration	0/3 (0%)	0	0/3 (0%)	0	1/31 (3.2%)	1
Hyponatremia	0/3 (0%)	0	0/3 (0%)	0	1/31 (3.2%)	1
Hyperuricemia	0/3 (0%)	0	0/3 (0%)	0	1/31 (3.2%)	1
Musculoskeletal and connective tissue disorders
Pain in extremity	0/3 (0%)	0	0/3 (0%)	0	1/31 (3.2%)	1
Pelvic soft tissue necrosis	0/3 (0%)	0	1/3 (33.3%)	1	0/31 (0%)	0
Nervous system disorders
Lightheadedness	0/3 (0%)	0	0/3 (0%)	0	1/31 (3.2%)	1
Convulsions	0/3 (0%)	0	0/3 (0%)	0	1/31 (3.2%)	1
Vasovalgal reaction	1/3 (33.3%)	1	0/3 (0%)	0	0/31 (0%)	0
Renal and urinary disorders
Acute kidney injury	0/3 (0%)	0	0/3 (0%)	0	1/31 (3.2%)	1
Respiratory, thoracic and mediastinal disorders
Dyspnea	0/3 (0%)	0	0/3 (0%)	0	1/31 (3.2%)	1
Hemoptysis	0/3 (0%)	0	0/3 (0%)	0	1/31 (3.2%)	1
Right lower lobe infiltrate	1/3 (33.3%)	1	0/3 (0%)	0	0/31 (0%)	0
Pleural effusion	1/3 (33.3%)	1	0/3 (0%)	0	0/31 (0%)	0
Pneumothorax	0/3 (0%)	0	0/3 (0%)	0	1/31 (3.2%)	4
Other (Not Including Serious) Adverse Events
	Phase 1 Cohort 1		Phase 1 Cohort 2		Phase 2
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/3 (100%)		3/3 (100%)		31/31 (100%)
Blood and lymphatic system disorders
Anemia	0/3 (0%)	0	1/3 (33.3%)	1	6/31 (19.4%)	8
Leukocytosis	0/3 (0%)	0	0/3 (0%)	0	2/31 (6.5%)	4
Hemoptysis	1/3 (33.3%)	1	0/3 (0%)	0	0/31 (0%)	0
Cardiac disorders
Sinus tachycardia	0/3 (0%)	0	0/3 (0%)	0	2/31 (6.5%)	3
Incomplete Right Bundle Branch Lock	0/3 (0%)	0	1/3 (33.3%)	1	0/31 (0%)	0
Sinus bradycardia	0/3 (0%)	0	1/3 (33.3%)	1	0/31 (0%)	0
Ear and labyrinth disorders
Ear pain	0/3 (0%)	0	0/3 (0%)	0	2/31 (6.5%)	2
Glaucoma	1/3 (33.3%)	1	0/3 (0%)	0	0/31 (0%)	0
Endocrine disorders
Hypothyroidism	0/3 (0%)	0	0/3 (0%)	0	8/31 (25.8%)	11
Hyperthyroidism	0/3 (0%)	0	1/3 (33.3%)	1	3/31 (9.7%)	3
Eye disorders
Dry Eye	1/3 (33.3%)	1	3/3 (100%)	3	5/31 (16.1%)	5
Blurred Vision	1/3 (33.3%)	1	0/3 (0%)	0	4/31 (12.9%)	4
Conjunctivitis	0/3 (0%)	0	1/3 (33.3%)	2	2/31 (6.5%)	2
Eye Pain	0/3 (0%)	0	2/3 (66.7%)	2	0/31 (0%)	0
Bilateral anterior uveitis	1/3 (33.3%)	1	0/3 (0%)	0	0/31 (0%)	0
Gastrointestinal disorders
Nausea	3/3 (100%)	3	3/3 (100%)	3	27/31 (87.1%)	37
Constipation	1/3 (33.3%)	1	3/3 (100%)	3	12/31 (38.7%)	16
Dry Mouth	1/3 (33.3%)	1	0/3 (0%)	0	14/31 (45.2%)	14
Vomiting	1/3 (33.3%)	1	3/3 (100%)	3	9/31 (29%)	12
Mucositis oral	0/3 (0%)	0	2/3 (66.7%)	3	12/31 (38.7%)	16
Diarrhea	0/3 (0%)	0	2/3 (66.7%)	2	7/31 (22.6%)	13
Abdominal Pain	0/3 (0%)	0	0/3 (0%)	0	6/31 (19.4%)	9
Gastroesophageal reflux disease	1/3 (33.3%)	2	0/3 (0%)	0	2/31 (6.5%)	2
Sore throat	0/3 (0%)	0	0/3 (0%)	0	3/31 (9.7%)	3
Stomach pain	0/3 (0%)	0	0/3 (0%)	0	2/31 (6.5%)	2
Esophagitis	1/3 (33.3%)	1	1/3 (33.3%)	1	1/31 (3.2%)	1
Hemorrhoids	0/3 (0%)	0	0/3 (0%)	0	2/31 (6.5%)	2
Dental Caries	1/3 (33.3%)	1	0/3 (0%)	0	0/31 (0%)	0
Rectal Discharge	0/3 (0%)	0	1/3 (33.3%)	1	0/31 (0%)	0
Ascites	0/3 (0%)	0	0/3 (0%)	0	2/31 (6.5%)	8
General disorders
Fatigue	1/3 (33.3%)	1	3/3 (100%)	3	21/31 (67.7%)	26
Fever	1/3 (33.3%)	1	2/3 (66.7%)	2	13/31 (41.9%)	15
Pain	0/3 (0%)	0	1/3 (33.3%)	3	7/31 (22.6%)	7
Edema Limbs	1/3 (33.3%)	1	1/3 (33.3%)	1	6/31 (19.4%)	6
Chills	0/3 (0%)	0	1/3 (33.3%)	1	4/31 (12.9%)	4
Flu-like symptoms	1/3 (33.3%)	1	0/3 (0%)	0	3/31 (9.7%)	4
Non-cardiac chest pain	0/3 (0%)	0	0/3 (0%)	0	3/31 (9.7%)	4
Infusion Related Reaction	1/3 (33.3%)	1	0/3 (0%)	0	0/31 (0%)	0
Pain at Port Site	1/3 (33.3%)	1	0/3 (0%)	0	0/31 (0%)	0
Palatal inflammation	0/3 (0%)	0	1/3 (33.3%)	1	0/31 (0%)	0
Infections and infestations
Upper Respiratory Infection	0/3 (0%)	0	1/3 (33.3%)	1	8/31 (25.8%)	11
Urinary tract infection	0/3 (0%)	0	1/3 (33.3%)	1	3/31 (9.7%)	6
Otitis externa	1/3 (33.3%)	1	0/3 (0%)	0	1/31 (3.2%)	1
Tinea Pedis	1/3 (33.3%)	1	0/3 (0%)	0	0/31 (0%)	0
Paronychia	0/3 (0%)	0	1/3 (33.3%)	1	0/31 (0%)	0
Injury, poisoning and procedural complications
Bruising	0/3 (0%)	0	0/3 (0%)	0	2/31 (6.5%)	3
Investigations
Neutrophil Count Decreased	0/3 (0%)	0	2/3 (66.7%)	3	7/31 (22.6%)	13
Weight Loss	0/3 (0%)	0	1/3 (33.3%)	1	7/31 (22.6%)	18
Creatinine increased	0/3 (0%)	0	1/3 (33.3%)	1	3/31 (9.7%)	4
White blood cell decreased	0/3 (0%)	0	1/3 (33.3%)	1	2/31 (6.5%)	2
Alanine aminotransferase increase	0/3 (0%)	0	0/3 (0%)	0	2/31 (6.5%)	4
Aspartate aminotransferase increased	0/3 (0%)	0	0/3 (0%)	0	2/31 (6.5%)	2
Lymphocyte count decreased	1/3 (33.3%)	1	1/3 (33.3%)	1	0/31 (0%)	0
Metabolism and nutrition disorders
Anorexia	2/3 (66.7%)	3	2/3 (66.7%)	3	14/31 (45.2%)	19
Hypomagnesemia	0/3 (0%)	0	2/3 (66.7%)	2	7/31 (22.6%)	9
Hypokalemia	0/3 (0%)	0	0/3 (0%)	0	8/31 (25.8%)	8
Hypoalbuminemia	0/3 (0%)	0	0/3 (0%)	0	5/31 (16.1%)	6
Hypocalcemia	0/3 (0%)	0	0/3 (0%)	0	4/31 (12.9%)	5
Hypophosphatemia	0/3 (0%)	0	0/3 (0%)	0	3/31 (9.7%)	3
Hyperuricemia	0/3 (0%)	0	0/3 (0%)	0	2/31 (6.5%)	4
Dehydration	0/3 (0%)	0	1/3 (33.3%)	1	0/31 (0%)	0
Musculoskeletal and connective tissue disorders
Bone Pain	0/3 (0%)	0	0/3 (0%)	0	8/31 (25.8%)	9
Back Pain	1/3 (33.3%)	1	0/3 (0%)	0	7/31 (22.6%)	7
Pain in Extremity	1/3 (33.3%)	1	0/3 (0%)	0	8/31 (25.8%)	11
Generalized muscle weakness	0/3 (0%)	0	0/3 (0%)	0	5/31 (16.1%)	5
Arthralgia	0/3 (0%)	0	1/3 (33.3%)	2	2/31 (6.5%)	2
Right Hip Pain	0/3 (0%)	0	0/3 (0%)	0	2/31 (6.5%)	2
Joint Pain	0/3 (0%)	0	0/3 (0%)	0	2/31 (6.5%)	2
Left Shoulder Pain	1/3 (33.3%)	1	0/3 (0%)	0	0/31 (0%)	0
Rib Pain	1/3 (33.3%)	1	0/3 (0%)	0	0/31 (0%)	0
Shoulder Sprain	0/3 (0%)	0	1/3 (33.3%)	1	0/31 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Tumor Pain	1/3 (33.3%)	2	0/3 (0%)	0	5/31 (16.1%)	7
Squamous Cell Carcinoma In Situ	1/3 (33.3%)	1	0/3 (0%)	0	0/31 (0%)	0
Nervous system disorders
Dysgeusia	1/3 (33.3%)	1	2/3 (66.7%)	3	9/31 (29%)	9
Headache	0/3 (0%)	0	0/3 (0%)	0	12/31 (38.7%)	16
Dizziness	1/3 (33.3%)	1	1/3 (33.3%)	1	5/31 (16.1%)	7
Lightheadedness	0/3 (0%)	0	0/3 (0%)	0	2/31 (6.5%)	3
Paresthesia	0/3 (0%)	0	0/3 (0%)	0	2/31 (6.5%)	2
Somnolence	0/3 (0%)	0	0/3 (0%)	0	2/31 (6.5%)	2
Neuropathy	0/3 (0%)	0	0/3 (0%)	0	2/31 (6.5%)	2
Dysphasia	1/3 (33.3%)	1	0/3 (0%)	0	0/31 (0%)	0
Restless Legs	1/3 (33.3%)	1	0/3 (0%)	0	1/31 (3.2%)	1
Delayed word recall	1/3 (33.3%)	1	0/3 (0%)	0	0/31 (0%)	0
Right Upper Extremity Numbness	1/3 (33.3%)	1	0/3 (0%)	0	0/31 (0%)	0
Left Upper Extremity Numbness	1/3 (33.3%)	1	0/3 (0%)	0	0/31 (0%)	0
Psychiatric disorders
Insomnia	0/3 (0%)	0	2/3 (66.7%)	2	7/31 (22.6%)	8
Anxiety	0/3 (0%)	0	1/3 (33.3%)	1	7/31 (22.6%)	7
Depression	0/3 (0%)	0	0/3 (0%)	0	5/31 (16.1%)	5
Renal and urinary disorders
Hematuria	0/3 (0%)	0	1/3 (33.3%)	1	1/31 (3.2%)	1
Urinary frequency	0/3 (0%)	0	0/3 (0%)	0	2/31 (6.5%)	2
Reproductive system and breast disorders
Erectile dysfunction	1/3 (33.3%)	1	1/3 (33.3%)	1	2/31 (6.5%)	2
Respiratory, thoracic and mediastinal disorders
Cough	2/3 (66.7%)	2	1/3 (33.3%)	1	11/31 (35.5%)	12
Dyspnea	0/3 (0%)	0	1/3 (33.3%)	1	9/31 (29%)	11
Pleural Effusion	1/3 (33.3%)	1	1/3 (33.3%)	2	4/31 (12.9%)	4
Postnasal drip	1/3 (33.3%)	1	1/3 (33.3%)	1	2/31 (6.5%)	2
Rhinorrhea	0/3 (0%)	0	0/3 (0%)	0	3/31 (9.7%)	3
Hiccups	0/3 (0%)	0	0/3 (0%)	0	3/31 (9.7%)	7
Hypoxia	0/3 (0%)	0	0/3 (0%)	0	2/31 (6.5%)	2
Nasal congestion	0/3 (0%)	0	0/3 (0%)	0	2/31 (6.5%)	2
Epistaxis	0/3 (0%)	0	1/3 (33.3%)	1	0/31 (0%)	0
Productive Cough	0/3 (0%)	0	1/3 (33.3%)	1	0/31 (0%)	0
Skin and subcutaneous tissue disorders
Alopecia	1/3 (33.3%)	1	2/3 (66.7%)	2	11/31 (35.5%)	11
Pruritis	1/3 (33.3%)	1	1/3 (33.3%)	1	8/31 (25.8%)	9
Rash Maculo-papular	1/3 (33.3%)	1	2/3 (66.7%)	2	3/31 (9.7%)	4
Rash	1/3 (33.3%)	1	0/3 (0%)	0	5/31 (16.1%)	7
Dry Skin	2/3 (66.7%)	2	0/3 (0%)	0	3/31 (9.7%)	3
Nail discoloration	0/3 (0%)	0	0/3 (0%)	0	4/31 (12.9%)	4
Erythema	0/3 (0%)	0	0/3 (0%)	0	3/31 (9.7%)	4
Skin Ulceration	0/3 (0%)	0	0/3 (0%)	0	2/31 (6.5%)	2
Bump on Elbow	1/3 (33.3%)	1	0/3 (0%)	0	0/31 (0%)	0
Eczema	1/3 (33.3%)	1	0/3 (0%)	0	0/31 (0%)	0
Actinic Keratosis	1/3 (33.3%)	1	0/3 (0%)	0	0/31 (0%)	0
Seborrheic keratosis	1/3 (33.3%)	1	0/3 (0%)	0	0/31 (0%)	0
Small Bump on Right Shoulder	1/3 (33.3%)	1	0/3 (0%)	0	0/31 (0%)	0
Skin Sensitivity	1/3 (33.3%)	1	0/3 (0%)	0	0/31 (0%)	0
Sebaceous cyst	0/3 (0%)	0	1/3 (33.3%)	1	0/31 (0%)	0
Vascular disorders
Hypertension	1/3 (33.3%)	1	0/3 (0%)	0	2/31 (6.5%)	2
Hypotension	0/3 (0%)	0	0/3 (0%)	0	2/31 (6.5%)	4
Thromboembolic event	1/3 (33.3%)	1	0/3 (0%)	0	1/31 (3.2%)	1
Hot flashes	0/3 (0%)	0	0/3 (0%)	0	2/31 (6.5%)	2
Hematoma	0/3 (0%)	0	1/3 (33.3%)	1	0/31 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.