To Determine the Safety of Regorafenib, Hydroxychloroquine, and Entinostat Metastatic Colorectal Cancer

• ClinicalTrials.gov Identifier: NCT03215264
• Recruitment Status: Completed
• First Posted: July 12, 2017
• Results First Posted: November 9, 2023
• Last Update Posted: November 9, 2023
• Sponsor: Abramson Cancer Center at Penn Medicine
• Information provided by (Responsible Party): Abramson Cancer Center at Penn Medicine

Study Description

Brief Summary:

The main purpose of this study is to find the best dose of hydroxychloroquine (HCQ) when given in combination with regorafenib and entinostat.

Condition or disease	Intervention/treatment	Phase
Colorectal Cancer	Drug: hydroxychloroquine; Drug: entinostat; Drug: regorafenib	Phase 1

Detailed Description:

This was a 3+3 phase I trial of HCQ and entinostat with regorafenib in patients with metastatic CRC. The primary objective was safety and the secondary objective was clinical efficacy. The trial was intended to be a Phase 1/2 trial, but the trial never moved forward to Phase 2.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 20 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Intervention Model Description: Standard 3+3 design to determine the maximum tolerated dose
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase I/II Trial of Regorafenib, Hydroxychloroquine, and Entinostat in Metastatic Colorectal Cancer
• Actual Study Start Date: October 2, 2017
• Actual Primary Completion Date: June 1, 2020
• Actual Study Completion Date: June 1, 2020

Arms and Interventions

Arm	Intervention/treatment
Experimental: Dose level 1; Regorafenib 160mg daily 1-21 of 28-day cycle , Entinostat 3mg weekly, HCQ 600mg daily.	Drug: hydroxychloroquine; 600-1200mg daily; Other Name: Plaquenil · Quineprox; Drug: entinostat; 3-5mg weekly; Other Name: DB11841; Drug: regorafenib; 160mg daily; Other Name: Stivarga
Experimental: Dose level 2; Regorafenib 160mg daily 1-21 of 28-day cycle Entinostat 5mg weekly, HCQ 600mg daily	Drug: hydroxychloroquine; 600-1200mg daily; Other Name: Plaquenil · Quineprox; Drug: entinostat; 3-5mg weekly; Other Name: DB11841; Drug: regorafenib; 160mg daily; Other Name: Stivarga
Experimental: Dose level 3; Regorafenib 160mg daily 1-21 of 28-day cycle, Entinostat 5mg weekly, HCQ 600mg BID (1200mg daily).	Drug: hydroxychloroquine; 600-1200mg daily; Other Name: Plaquenil · Quineprox; Drug: entinostat; 3-5mg weekly; Other Name: DB11841; Drug: regorafenib; 160mg daily; Other Name: Stivarga

Outcome Measures

Primary Outcome Measures :

1. Maximum Tolerated Dose (MTD) of Hydroxychloroquine and Entinostat in Combination With Regorafenib [ Time Frame: 18 months ]
   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.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Histologic or cytologic confirmation of metastatic colorectal cancer
• Measurable disease based on modified RECIST 1.1 criteria
• Patients should have received adequate therapy with prior 5-fluorouracil, oxaliplatin, and irinotecan, unless contra-indicated, not tolerated or declined.
• No prior therapy with regorafenib or other anti-angiogenic tyrosine kinase inhibitor
• No prior or current therapy with an HDAC inhibitor
• Age 18 years or older
• ECOG performance status of 0 or 1
• If a female of childbearing potential, has a negative serum blood pregnancy test during screening and a negative urine pregnancy test within 3 days prior to receiving the first dose of study drug. If the screening serum test is done within 3 days prior to receiving the first dose of study drug, a urine test is not required. If a patient is of childbearing potential the patient must agree to use effective contraception (see Appendix C for acceptable methods) during the study and for 120 days after the last dose of study drug. Non-childbearing potential is defined as (by other than medical reasons):
• ≥45 years of age and has not had menses for >2 years
• Amenorrheic for <2 years without a hysterectomy and oophorectomy and a follicle-stimulating hormone value in the postmenopausal range upon pre-study (screening) evaluation
• Post hysterectomy, oophorectomy or tubal ligation. Documented hysterectomy or oophorectomy must be confirmed with medical records of the actual procedure or confirmed by an ultrasound. Tubal ligation must be confirmed with medical records of the actual procedure otherwise the patient must be willing to use 2 adequate barrier methods throughout the study, starting with the screening visit through 120 days after the last dose of study drug
• If male, agrees to use an adequate method of contraception starting with the first dose of study drug through 120 days after the last dose of study drug
• Life expectancy of greater than 3 months
• Patients must have the ability to understand and the willingness to sign a written informed consent document.

• Adequate bone-marrow, liver, and renal function as assessed by the following laboratory requirements within 4 weeks of starting treatment

  • Absolute neutrophil count >1,500 per uL
  • Hemoglobin > 9 g/dL
  • Platelets >100,000 per uL
  • Creatinine < 1.5 x ULN OR Creatinine clearance (CrCl) > 60 by Cockcroft-Gault Equation if Creatinine >1.5
  • AST and ALT < 2.5 x ULN (< 5 x ULN if documented liver metastases)
  • Total bilirubin <1.5 ULN OR direct bilirubin < ULN if total bilirubin > 1.5 x ULN
  • INR < 2.0
• Experienced resolution of toxic effect(s) of the most recent prior anti-cancer therapy to Grade <1 (except alopecia or neuropathy). If patient underwent major surgery or radiation therapy of >30 Gy, they must have recovered from the toxicity and/or complications from the intervention.

Exclusion Criteria

• History or current evidence of any condition, therapy or laboratory abnormality that might confound the results of the study, interfere with the patient's participation for the full duration of the study, or is not in the best interest of the patient to participate, in the opinion of the treating Investigator, including, but not limited to:

  1. Myocardial infarction or arterial thromboembolic events within 6 months prior to screening or severe or unstable angina, New York Heart Association (NYHA) Class III or IV disease, or a QTc interval > 470 msec.
  2. Uncontrolled hypertension or diabetes mellitus.
  3. Another known malignancy that is progressing or requires active treatment.
  4. Any prior history of other cancer within the prior 5 years with the exception of adequately treated basal cell carcinoma or cervical intraepithelial neoplasia [CIN]/cervical carcinoma in situ or melanoma in situ).
  5. Active infection requiring systemic therapy
  6. Known active central nervous system (CNS) metastases and/or carcinomatous meningitis.
• Any contraindication to oral agents or significant nausea and vomiting, malabsorption, or significant small bowel resection that, in the opinion of the investigator, would preclude adequate absorption.
• Allergy to benzamide, inactive components of entinostat, or any of the other administered therapies
• Known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the study.
• Currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks of the first dose of study drug.
• If female, is pregnant or breastfeeding.
• Known G6PD deficiency, severe psoriasis, porphyria, macular degeneration, or severe diabetic retinopathy due to greater potential HCQ toxicity
• Patients with pre-existing hypertension should be on a stable antihypertensive regimen and have a blood pressure ≤ 150/100 mmHg at the time of enrollment.
• Evidence or history of bleeding diathesis. Any hemorrhage or bleeding event of CTCAE grade 3 or higher within 4 weeks of start of study medication
• Non-healing wound, ulcer, or bone fracture
• Patients using warfarin are excluded. Patients using other oral or parenteral anticoagulation are not excluded provided they are on a stable dose of anticoagulant but must undergo more frequent platelet count monitoring.

Contacts and Locations

Locations

United States, Pennsylvania

Abramson Cancer Center of the University of Pennsylvania

Philadelphia, Pennsylvania, United States, 19104

Sponsors and Collaborators

Abramson Cancer Center at Penn Medicine

Investigators

• Principal Investigator: Peter O'Dwyer, MD; Abramson Cancer Center at Penn Medicine

  Study Documents (Full-Text)

Documents provided by Abramson Cancer Center at Penn Medicine:

Study Protocol and Statistical Analysis Plan  [PDF] June 15, 2017

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Karasic TB, Brown TJ, Schneider C, Teitelbaum UR, Reiss KA, Mitchell TC, Massa RC, O'Hara MH, DiCicco L, Garcia-Marcano L, Amaravadi RK, O'Dwyer PJ. Phase I Trial of Regorafenib, Hydroxychloroquine, and Entinostat in Metastatic Colorectal Cancer. Oncologist. 2022 Sep 2;27(9):716-e689. doi: 10.1093/oncolo/oyac078.

• Responsible Party: Abramson Cancer Center at Penn Medicine
• ClinicalTrials.gov Identifier: NCT03215264
• Other Study ID Numbers: UPCC 31216
• First Posted: July 12, 2017
• Results First Posted: November 9, 2023
• Last Update Posted: November 9, 2023
• Last Verified: January 2023

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Colorectal Neoplasms; Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Rectal Diseases; Hydroxychloroquine; Entinostat; Antimalarials; Antiprotozoal Agents; Antiparasitic Agents; Anti-Infective Agents; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Antirheumatic Agents; Antineoplastic Agents; Histone Deacetylase Inhibitors