Regorafenib, Hydroxychloroquine, and Entinostat in Treating Patients with Metastatic Colorectal Cancer

Status: Active


This phase I / II trial studies the side effects and best dose of hydroxychloroquine and entinostat when given together with regorafenib, and to see how well they work in treating patients with colorectal cancer that has spread to other places in the body. Hydroxychloroquine may help decrease resistance to chemotherapy, entinostat may help to disrupt the signaling of cancer cells, and regorafenib may help to decrease the blood supply of a tumor. Giving hydroxychloroquine, entinostat, and regorafenib together may work better in treating patients with colorectal cancer.

Eligibility Criteria

Inclusion Criteria

  • Histologic or cytologic confirmation of metastatic colorectal cancer
  • Measurable disease based on modified Response Evaluation Criteria in Solid Tumors (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 a histone deacetylase (HDAC) inhibitor
  • Eastern Cooperative Oncology Group (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 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
  • Absolute neutrophil count >= 1,500 per uL (within 4 weeks of starting treatment)
  • Hemoglobin >= 9 g/dL (within 4 weeks of starting treatment)
  • Platelets >= 100,000 per uL (within 4 weeks of starting treatment)
  • Creatinine =< 1.5 x upper limit of normal (ULN) OR creatinine clearance (CrCl) >= 60 by Cockcroft-Gault equation if creatinine > 1.5 (within 4 weeks of starting treatment)
  • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x ULN (=< 5 x ULN if documented liver metastases) (within 4 weeks of starting treatment)
  • Total bilirubin =< 1.5 ULN OR direct bilirubin =< ULN if total bilirubin > 1.5 x ULN (within 4 weeks of starting treatment)
  • Institutional normalized ratio (INR) =< 2.0 (within 4 weeks of starting treatment)
  • 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: * 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 * Uncontrolled hypertension or diabetes mellitus * Another known malignancy that is progressing or requires active treatment * 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) * Active infection requiring systemic therapy * 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 Common Terminology Criteria for Adverse Events (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

Locations & Contacts


University of Pennsylvania / Abramson Cancer Center
Status: Active
Contact: Peter James O'Dwyer

Trial Objectives and Outline


I. To determine doses of hydroxychloroquine and entinostat with acceptable toxicity in combination with regorafenib. (Phase I)

II. To determine the response rate of a three drug combination of regorafenib, hydroxychloroquine, and entinostat in patients with colorectal cancer that has progressed on standard agents. (Phase II)


I. To describe the toxicity profile of the three drug combination.

II. To measure overall survival, progression-free survival, and duration of response.

III. To describe mutational profiles of responders and non-responders using next-generation sequencing.

IV. To evaluate the pharmacodynamics of entinostat by measuring protein lysine acetylation in peripheral blood mononuclear cells (PBMCs), and lymphocyte subsets.

V. To assess and quantitate autophagy pharmacodynamics using Western blotting of PBMC extracts and serum markers.

VI. To describe gene expression alterations as result of therapy using paired biopsy specimens at baseline and 3 weeks. (Phase II)

VII. To analyze FOXO1 expression and subcellular localization as a marker of treatment effect using paired biopsy specimens at baseline and 3 weeks. (Phase II)

OUTLINE: This is phase I, dose-escalation study of hydroxychloroquine sulfate and entinostat followed by a phase II study.

Patients receive regorafenib orally (PO) daily on days 1-21, entinostat PO on days 1, 8, 15, and 22, and hydroxychloroquine sulfate PO twice daily (BID) on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Trial Phase & Type

Trial Phase

Phase I/II

Trial Type


Lead Organization

Lead Organization
University of Pennsylvania / Abramson Cancer Center

Principal Investigator
Peter James O'Dwyer

Trial IDs

Primary ID UPCC 31216
Secondary IDs NCI-2018-02068 ID NCT03215264