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

NCT03215264 | Completed Phase 1 Results DMC FDA Drug

• 1 other identifier: UPCC 31216
• Study Type: interventional
• Target: 20
• Locations: 1 country
• Sites: 1

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.

Conditions

Colorectal Cancer

Outcome Measures

Primary Outcomes (1)

• Maximum Tolerated Dose (MTD) of Hydroxychloroquine and Entinostat in Combination With Regorafenib

  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.

  18 months

Study Arms (3)

Dose level 1

EXPERIMENTAL

Regorafenib 160mg daily 1-21 of 28-day cycle , Entinostat 3mg weekly, HCQ 600mg daily.

Drug: hydroxychloroquine; Drug: entinostat; Drug: regorafenib

Dose level 2

EXPERIMENTAL

Regorafenib 160mg daily 1-21 of 28-day cycle Entinostat 5mg weekly, HCQ 600mg daily

Drug: hydroxychloroquine; Drug: entinostat; Drug: regorafenib

Dose level 3

EXPERIMENTAL

Regorafenib 160mg daily 1-21 of 28-day cycle, Entinostat 5mg weekly, HCQ 600mg BID (1200mg daily).

Drug: hydroxychloroquine; Drug: entinostat; Drug: regorafenib

Interventions

hydroxychloroquine DRUG

600-1200mg daily

Also known as: Plaquenil · Quineprox

Dose level 1; Dose level 2; Dose level 3

entinostat DRUG

3-5mg weekly

Also known as: DB11841

Dose level 1; Dose level 2; Dose level 3

regorafenib DRUG

160mg daily

Also known as: Stivarga

Dose level 1; Dose level 2; Dose level 3

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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 CTCAE grade 3 or higher within 4 weeks of start of study medication

Sponsors & Collaborators

• Abramson Cancer Center at Penn Medicine: lead

Study Sites (1)

Abramson Cancer Center of the University of Pennsylvania

Philadelphia, Pennsylvania, 19104, United States

Location

Related Publications (1)

• 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.

  PMID: 35552447 DERIVED

MeSH Terms

Conditions

Colorectal Neoplasms

Interventions

Hydroxychloroquine; entinostat; regorafenib

Condition Hierarchy (Ancestors)

Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Rectal Diseases

Intervention Hierarchy (Ancestors)

Chloroquine; Aminoquinolines; Quinolines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Results Point of Contact

• Title: Thomas Karasic, MD
• Organization: University of Pennsylvania/ Abramson Cancer Center

thomas.karasic@pennmedicine.upenn.edu

2156141858

Study Officials

• Peter O'Dwyer, MD

  Abramson Cancer Center at Penn Medicine

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: LTE60
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Standard 3+3 design to determine the maximum tolerated dose

Study Record Dates

• First Submitted: July 10, 2017
• First Posted: July 12, 2017
• Study Start: October 2, 2017
• Primary Completion: June 1, 2020
• Study Completion: June 1, 2020
• Last Updated: November 9, 2023
• Results First Posted: November 9, 2023

Record last verified: 2023-01

Locations

US (1)