Trial Outcomes & Findings for To Determine the Safety of Regorafenib, Hydroxychloroquine, and Entinostat Metastatic Colorectal Cancer (NCT NCT03215264)
NCT ID: NCT03215264
Last Updated: 2023-11-09
Results Overview
Participants were evaluable for toxicity if they have taken one dose of HCQ and one dose of entinostat. To be considered for evaluability in a Phase I cohort in the absence of dose-limiting toxicity, patients should have completed \> 85% of HCQ doses, and at least 3 of 4 entinostat doses. The MTD will be defined as a) the dose producing DLT in 1 out of 6 patients, or b) the dose level below the dose which produced DLT in ≥ 2 out of 3 patients, or in ≥ 2 out of 6 patients. DLTs will be defined by toxicity occurring during the first 4 weeks of this study.
Recruitment status
COMPLETED
Study phase
PHASE1
Target enrollment
20 participants
Primary outcome timeframe
18 months
Results posted on
2023-11-09
Participant Flow
Participant milestones
| Measure |
Dose Level 1
hydroxychloroquine: 600mg daily
entinostat: 3mg weekly
regorafenib: 160mg daily
|
Dose Level 2
hydroxychloroquine: 600mg daily
entinostat: 5mg weekly
regorafenib: 160mg daily
|
Dose Level 3
hydroxychloroquine: 1200mg daily
entinostat: 5mg weekly
regorafenib: 160mg daily
|
|---|---|---|---|
|
Dose Level 1
STARTED
|
6
|
0
|
0
|
|
Dose Level 1
COMPLETED
|
6
|
0
|
0
|
|
Dose Level 1
NOT COMPLETED
|
0
|
0
|
0
|
|
Dose Level 2
STARTED
|
0
|
7
|
0
|
|
Dose Level 2
COMPLETED
|
0
|
6
|
0
|
|
Dose Level 2
NOT COMPLETED
|
0
|
1
|
0
|
|
Dose Level 3
STARTED
|
0
|
0
|
7
|
|
Dose Level 3
COMPLETED
|
0
|
0
|
6
|
|
Dose Level 3
NOT COMPLETED
|
0
|
0
|
1
|
Reasons for withdrawal
| Measure |
Dose Level 1
hydroxychloroquine: 600mg daily
entinostat: 3mg weekly
regorafenib: 160mg daily
|
Dose Level 2
hydroxychloroquine: 600mg daily
entinostat: 5mg weekly
regorafenib: 160mg daily
|
Dose Level 3
hydroxychloroquine: 1200mg daily
entinostat: 5mg weekly
regorafenib: 160mg daily
|
|---|---|---|---|
|
Dose Level 2
Adverse Event
|
0
|
1
|
0
|
|
Dose Level 3
Withdrawal by Subject
|
0
|
0
|
1
|
Baseline Characteristics
To Determine the Safety of Regorafenib, Hydroxychloroquine, and Entinostat Metastatic Colorectal Cancer
Baseline characteristics by cohort
| Measure |
Dose Level 1
n=6 Participants
Regorafenib: 160mg daily 1-21 of 28 day cycle (with provisions to lower the starting dose to 80mg if toxicity is excessive)
entinostat: 3mg weekly
hydroxychloroquine: 600 daily
|
Dose Level 2
n=7 Participants
Regorafenib: 160mg daily 1-21 of 28 day cycle (with provisions to lower the starting dose to 80mg if toxicity is excessive)
entinostat: 5mg weekly
hydroxychloroquine: 600 daily
|
Dose Level 3
n=7 Participants
Regorafenib: 160mg daily 1-21 of 28 day cycle (with provisions to lower the starting dose to 80mg if toxicity is excessive)
entinostat: 5mg weekly
hydroxychloroquine: 1200mg daily
|
Total
n=20 Participants
Total of all reporting groups
|
|---|---|---|---|---|
|
Age, Continuous
|
65 years
n=113 Participants
|
60 years
n=163 Participants
|
69 years
n=160 Participants
|
64.5 years
n=483 Participants
|
|
Sex: Female, Male
Female
|
3 Participants
n=113 Participants
|
3 Participants
n=163 Participants
|
4 Participants
n=160 Participants
|
10 Participants
n=483 Participants
|
|
Sex: Female, Male
Male
|
3 Participants
n=113 Participants
|
4 Participants
n=163 Participants
|
3 Participants
n=160 Participants
|
10 Participants
n=483 Participants
|
|
Ethnicity (NIH/OMB)
Hispanic or Latino
|
0 Participants
n=113 Participants
|
0 Participants
n=163 Participants
|
0 Participants
n=160 Participants
|
0 Participants
n=483 Participants
|
|
Ethnicity (NIH/OMB)
Not Hispanic or Latino
|
6 Participants
n=113 Participants
|
7 Participants
n=163 Participants
|
7 Participants
n=160 Participants
|
20 Participants
n=483 Participants
|
|
Ethnicity (NIH/OMB)
Unknown or Not Reported
|
0 Participants
n=113 Participants
|
0 Participants
n=163 Participants
|
0 Participants
n=160 Participants
|
0 Participants
n=483 Participants
|
|
Race (NIH/OMB)
American Indian or Alaska Native
|
0 Participants
n=113 Participants
|
0 Participants
n=163 Participants
|
0 Participants
n=160 Participants
|
0 Participants
n=483 Participants
|
|
Race (NIH/OMB)
Asian
|
0 Participants
n=113 Participants
|
0 Participants
n=163 Participants
|
0 Participants
n=160 Participants
|
0 Participants
n=483 Participants
|
|
Race (NIH/OMB)
Native Hawaiian or Other Pacific Islander
|
0 Participants
n=113 Participants
|
0 Participants
n=163 Participants
|
0 Participants
n=160 Participants
|
0 Participants
n=483 Participants
|
|
Race (NIH/OMB)
Black or African American
|
1 Participants
n=113 Participants
|
0 Participants
n=163 Participants
|
1 Participants
n=160 Participants
|
2 Participants
n=483 Participants
|
|
Race (NIH/OMB)
White
|
5 Participants
n=113 Participants
|
7 Participants
n=163 Participants
|
6 Participants
n=160 Participants
|
18 Participants
n=483 Participants
|
|
Race (NIH/OMB)
More than one race
|
0 Participants
n=113 Participants
|
0 Participants
n=163 Participants
|
0 Participants
n=160 Participants
|
0 Participants
n=483 Participants
|
|
Race (NIH/OMB)
Unknown or Not Reported
|
0 Participants
n=113 Participants
|
0 Participants
n=163 Participants
|
0 Participants
n=160 Participants
|
0 Participants
n=483 Participants
|
|
Region of Enrollment
United States
|
6 participants
n=113 Participants
|
7 participants
n=163 Participants
|
7 participants
n=160 Participants
|
20 participants
n=483 Participants
|
PRIMARY outcome
Timeframe: 18 monthsParticipants were evaluable for toxicity if they have taken one dose of HCQ and one dose of entinostat. To be considered for evaluability in a Phase I cohort in the absence of dose-limiting toxicity, patients should have completed \> 85% of HCQ doses, and at least 3 of 4 entinostat doses. The MTD will be defined as a) the dose producing DLT in 1 out of 6 patients, or b) the dose level below the dose which produced DLT in ≥ 2 out of 3 patients, or in ≥ 2 out of 6 patients. DLTs will be defined by toxicity occurring during the first 4 weeks of this study.
Outcome measures
| Measure |
All Participants
n=20 Participants
All participants who received at least 1 dose of hydroxychloroquine 1 dose of entinostat.
|
|---|---|
|
Maximum Tolerated Dose (MTD) of Hydroxychloroquine and Entinostat in Combination With Regorafenib
Hydroxychloroquine Daily
|
1200 mg
|
|
Maximum Tolerated Dose (MTD) of Hydroxychloroquine and Entinostat in Combination With Regorafenib
Entinostat weekly
|
5 mg
|
Adverse Events
Dose Level 1
Serious events: 1 serious events
Other events: 6 other events
Deaths: 0 deaths
Dose Level 2
Serious events: 0 serious events
Other events: 7 other events
Deaths: 0 deaths
Dose Level 3
Serious events: 6 serious events
Other events: 7 other events
Deaths: 0 deaths
Serious adverse events
| Measure |
Dose Level 1
n=6 participants at risk
hydroxychloroquine: 600mg daily
entinostat: 3mg weekly
regorafenib: 160mg daily
|
Dose Level 2
n=7 participants at risk
hydroxychloroquine: 600mg daily
entinostat: 5mg weekly
regorafenib: 160mg daily
|
Dose Level 3
n=7 participants at risk
hydroxychloroquine: 1200mg daily
entinostat: 5mg weekly
regorafenib: 160mg daily
|
|---|---|---|---|
|
Metabolism and nutrition disorders
Dehydration
|
0.00%
0/6 • up to 18 months
|
0.00%
0/7 • up to 18 months
|
14.3%
1/7 • Number of events 1 • up to 18 months
|
|
Nervous system disorders
Spasticity
|
16.7%
1/6 • Number of events 1 • up to 18 months
|
0.00%
0/7 • up to 18 months
|
0.00%
0/7 • up to 18 months
|
|
Vascular disorders
Thrombolicevent
|
0.00%
0/6 • up to 18 months
|
0.00%
0/7 • up to 18 months
|
14.3%
1/7 • Number of events 1 • up to 18 months
|
|
Musculoskeletal and connective tissue disorders
Myalgia
|
16.7%
1/6 • Number of events 1 • up to 18 months
|
0.00%
0/7 • up to 18 months
|
0.00%
0/7 • up to 18 months
|
|
Gastrointestinal disorders
Nausea
|
0.00%
0/6 • up to 18 months
|
0.00%
0/7 • up to 18 months
|
14.3%
1/7 • Number of events 2 • up to 18 months
|
|
Gastrointestinal disorders
Rectal Hemorrhage
|
0.00%
0/6 • up to 18 months
|
0.00%
0/7 • up to 18 months
|
14.3%
1/7 • Number of events 1 • up to 18 months
|
|
Gastrointestinal disorders
Abdominal Pain
|
0.00%
0/6 • up to 18 months
|
0.00%
0/7 • up to 18 months
|
14.3%
1/7 • Number of events 1 • up to 18 months
|
|
Gastrointestinal disorders
Vomiting
|
0.00%
0/6 • up to 18 months
|
0.00%
0/7 • up to 18 months
|
14.3%
1/7 • Number of events 2 • up to 18 months
|
|
Musculoskeletal and connective tissue disorders
Pain in extremity
|
0.00%
0/6 • up to 18 months
|
0.00%
0/7 • up to 18 months
|
14.3%
1/7 • Number of events 1 • up to 18 months
|
|
Metabolism and nutrition disorders
Hyponatremia
|
0.00%
0/6 • up to 18 months
|
0.00%
0/7 • up to 18 months
|
14.3%
1/7 • Number of events 1 • up to 18 months
|
|
Gastrointestinal disorders
Gastrointestinal pain
|
0.00%
0/6 • up to 18 months
|
0.00%
0/7 • up to 18 months
|
14.3%
1/7 • Number of events 1 • up to 18 months
|
Other adverse events
| Measure |
Dose Level 1
n=6 participants at risk
hydroxychloroquine: 600mg daily
entinostat: 3mg weekly
regorafenib: 160mg daily
|
Dose Level 2
n=7 participants at risk
hydroxychloroquine: 600mg daily
entinostat: 5mg weekly
regorafenib: 160mg daily
|
Dose Level 3
n=7 participants at risk
hydroxychloroquine: 1200mg daily
entinostat: 5mg weekly
regorafenib: 160mg daily
|
|---|---|---|---|
|
Blood and lymphatic system disorders
Anemia
|
16.7%
1/6 • up to 18 months
|
42.9%
3/7 • up to 18 months
|
42.9%
3/7 • up to 18 months
|
|
Gastrointestinal disorders
Bloating
|
16.7%
1/6 • up to 18 months
|
14.3%
1/7 • up to 18 months
|
0.00%
0/7 • up to 18 months
|
|
Gastrointestinal disorders
Abdominal Pain
|
0.00%
0/6 • up to 18 months
|
42.9%
3/7 • up to 18 months
|
0.00%
0/7 • up to 18 months
|
|
Gastrointestinal disorders
Diarrhea
|
16.7%
1/6 • up to 18 months
|
14.3%
1/7 • up to 18 months
|
28.6%
2/7 • up to 18 months
|
|
Gastrointestinal disorders
Flatulence
|
16.7%
1/6 • up to 18 months
|
0.00%
0/7 • up to 18 months
|
0.00%
0/7 • up to 18 months
|
|
Gastrointestinal disorders
Mucositis Oral
|
33.3%
2/6 • up to 18 months
|
0.00%
0/7 • up to 18 months
|
14.3%
1/7 • up to 18 months
|
|
Gastrointestinal disorders
Nausea
|
50.0%
3/6 • up to 18 months
|
42.9%
3/7 • up to 18 months
|
14.3%
1/7 • up to 18 months
|
|
Gastrointestinal disorders
Rectal Hemorrhage
|
0.00%
0/6 • up to 18 months
|
14.3%
1/7 • up to 18 months
|
0.00%
0/7 • up to 18 months
|
|
Gastrointestinal disorders
Vomiting
|
16.7%
1/6 • up to 18 months
|
28.6%
2/7 • up to 18 months
|
0.00%
0/7 • up to 18 months
|
|
General disorders
Fatigue
|
50.0%
3/6 • up to 18 months
|
42.9%
3/7 • up to 18 months
|
57.1%
4/7 • up to 18 months
|
|
General disorders
Fever
|
16.7%
1/6 • up to 18 months
|
0.00%
0/7 • up to 18 months
|
0.00%
0/7 • up to 18 months
|
|
General disorders
Gait Disturbance
|
0.00%
0/6 • up to 18 months
|
14.3%
1/7 • up to 18 months
|
0.00%
0/7 • up to 18 months
|
|
General disorders
Pain
|
16.7%
1/6 • up to 18 months
|
0.00%
0/7 • up to 18 months
|
0.00%
0/7 • up to 18 months
|
|
Infections and infestations
Mucosal Infection
|
16.7%
1/6 • up to 18 months
|
0.00%
0/7 • up to 18 months
|
14.3%
1/7 • up to 18 months
|
|
Infections and infestations
Papulopustular Rash
|
16.7%
1/6 • up to 18 months
|
0.00%
0/7 • up to 18 months
|
0.00%
0/7 • up to 18 months
|
|
Infections and infestations
Lung Infection
|
0.00%
0/6 • up to 18 months
|
0.00%
0/7 • up to 18 months
|
14.3%
1/7 • up to 18 months
|
|
Investigations
Weight loss
|
50.0%
3/6 • up to 18 months
|
42.9%
3/7 • up to 18 months
|
85.7%
6/7 • up to 18 months
|
|
Investigations
White Blood Cell Decreased
|
16.7%
1/6 • up to 18 months
|
42.9%
3/7 • up to 18 months
|
42.9%
3/7 • up to 18 months
|
|
Investigations
Blood bilirubin increased
|
33.3%
2/6 • up to 18 months
|
0.00%
0/7 • up to 18 months
|
0.00%
0/7 • up to 18 months
|
|
Investigations
Platelet Count Decreased
|
33.3%
2/6 • up to 18 months
|
28.6%
2/7 • up to 18 months
|
57.1%
4/7 • up to 18 months
|
|
Investigations
Alkaline Phosphate Increased
|
50.0%
3/6 • up to 18 months
|
14.3%
1/7 • up to 18 months
|
71.4%
5/7 • up to 18 months
|
|
Investigations
Aspartate Aminotransferase Increased
|
33.3%
2/6 • up to 18 months
|
0.00%
0/7 • up to 18 months
|
14.3%
1/7 • up to 18 months
|
|
Investigations
Alanine Aminotransferase Increased
|
0.00%
0/6 • up to 18 months
|
0.00%
0/7 • up to 18 months
|
14.3%
1/7 • up to 18 months
|
|
Investigations
Neutrophil count decreased
|
16.7%
1/6 • up to 18 months
|
14.3%
1/7 • up to 18 months
|
0.00%
0/7 • up to 18 months
|
|
Investigations
Thyroid Stimulating Hormone Increased
|
16.7%
1/6 • up to 18 months
|
0.00%
0/7 • up to 18 months
|
0.00%
0/7 • up to 18 months
|
|
Investigations
Lymphocyte count decreased
|
16.7%
1/6 • up to 18 months
|
0.00%
0/7 • up to 18 months
|
0.00%
0/7 • up to 18 months
|
|
Metabolism and nutrition disorders
Anorexia
|
33.3%
2/6 • up to 18 months
|
57.1%
4/7 • up to 18 months
|
42.9%
3/7 • up to 18 months
|
|
Metabolism and nutrition disorders
Hypophosphatemia
|
0.00%
0/6 • up to 18 months
|
0.00%
0/7 • up to 18 months
|
14.3%
1/7 • up to 18 months
|
|
Musculoskeletal and connective tissue disorders
Arthralgia
|
0.00%
0/6 • up to 18 months
|
14.3%
1/7 • up to 18 months
|
0.00%
0/7 • up to 18 months
|
|
Musculoskeletal and connective tissue disorders
Muscle Weakness Lower Limb
|
0.00%
0/6 • up to 18 months
|
14.3%
1/7 • up to 18 months
|
0.00%
0/7 • up to 18 months
|
|
Nervous system disorders
Dysgeusia
|
0.00%
0/6 • up to 18 months
|
14.3%
1/7 • up to 18 months
|
0.00%
0/7 • up to 18 months
|
|
Nervous system disorders
Headache
|
16.7%
1/6 • up to 18 months
|
0.00%
0/7 • up to 18 months
|
0.00%
0/7 • up to 18 months
|
|
Renal and urinary disorders
Urinary Frequency
|
0.00%
0/6 • up to 18 months
|
0.00%
0/7 • up to 18 months
|
14.3%
1/7 • up to 18 months
|
|
Respiratory, thoracic and mediastinal disorders
Hoarseness
|
0.00%
0/6 • up to 18 months
|
0.00%
0/7 • up to 18 months
|
28.6%
2/7 • up to 18 months
|
|
Respiratory, thoracic and mediastinal disorders
Dyspnea
|
0.00%
0/6 • up to 18 months
|
28.6%
2/7 • up to 18 months
|
0.00%
0/7 • up to 18 months
|
|
Respiratory, thoracic and mediastinal disorders
Cough
|
0.00%
0/6 • up to 18 months
|
14.3%
1/7 • up to 18 months
|
0.00%
0/7 • up to 18 months
|
|
Skin and subcutaneous tissue disorders
Palmer-plantar erthrodysesthesia
|
50.0%
3/6 • up to 18 months
|
14.3%
1/7 • up to 18 months
|
14.3%
1/7 • up to 18 months
|
|
Skin and subcutaneous tissue disorders
Rash acneiform
|
0.00%
0/6 • up to 18 months
|
14.3%
1/7 • up to 18 months
|
0.00%
0/7 • up to 18 months
|
|
Skin and subcutaneous tissue disorders
Puritus
|
0.00%
0/6 • up to 18 months
|
28.6%
2/7 • up to 18 months
|
0.00%
0/7 • up to 18 months
|
|
Skin and subcutaneous tissue disorders
Rash maculo-papular
|
0.00%
0/6 • up to 18 months
|
28.6%
2/7 • up to 18 months
|
14.3%
1/7 • up to 18 months
|
|
Vascular disorders
Hypotension
|
0.00%
0/6 • up to 18 months
|
14.3%
1/7 • up to 18 months
|
0.00%
0/7 • up to 18 months
|
Additional Information
Thomas Karasic, MD
University of Pennsylvania/ Abramson Cancer Center
Phone: 2156141858
Email: [email protected]
Results disclosure agreements
- Principal investigator is a sponsor employee
- Publication restrictions are in place
Restriction type: LTE60