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FOLFOX/Bevacizumab/Hydroxychloroquine (HCQ) in Colorectal Cancer

Primary Purpose

Rectal Cancer, Colon Cancer, Metastasis

Status

Completed

Phase

Phase 1

Locations

United States

Study Type

Interventional

Intervention

Hydroxychloroquine

Oxaliplatin

Leucovorin

5-fluorouracil

Bevacizumab

About this trial

This is an interventional treatment trial for Rectal Cancer focused on measuring histologically documented, advanced, metastatic, adenocarcinoma, colon, rectum

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Patients must have histologically documented advanced or metastatic adenocarcinoma of the colon or rectum.
Patients must have measurable disease as defined by the RECIST criteria as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded) as 20 mm with conventionaltechniques on either CT of MRI. Marker (CEA) elevation alone is insufficient for entry.
Patients may have had prior adjuvant treatment of advanced colorectal cancer. The prior treatment regimen must not have included bevacizumab but may have included oxaliplatin and the last dose of chemotherapy must have been 6 months prior to study entry. Patients with prior radiotherapy are acceptable. It must be at least 2 weeks since administration of radiation therapy and all signs of toxicty must have abated.
Patients must be 18 years or older.
Patients must have an ECOG performance status of 0-1.
The following required Initial Laboratory Values should be obtained within 4 weeks of the start of treatment: Granulocytes 1,500/ml, Platelet Count 100,000/ml, Creatinine 1.5 x upper limit of normal, Bilirubin 1.5 x upper limit of normal, AST 5 x upper limit of normal Urine Urine protein:creatinine ratio 1.0 at screening
Patients must not be pregnant or lactating as chemotherapy is thought to present substantial risk to the fetus/infant.
Patients must have a life expectancy of greater than three months.
Patients must have the ability to understand and the willingness to sign a written informed consent document.

Exclusion Criteria:

Major sugical procedure, open biopsy, or significant traumatic injury within 28 days prior to Day 0, anticipation of need for major surgical procedure during the course of the study. Minor surgical procedures such as fine needle aspirations or core biopsies within 7 days prior to Day 0.
Patients with serious nonhealing wounds, ulcers, or bone fractures.
Patients with a history of abdominal fistula, gastrointestinal perforation or intra-abdominal abscess within 6 months prior to Day 0
Patients with a history of myocardial infarction, unstable angina, or cerebrovascular accident 6 months prior to registration.
Patients with clinically significant peripheral vascular disease.
Patients with New York Heart Association Class II or greater congestive heart failure (class II is defined as symptoms of fatigue, dyspnea or other symptoms with ordinary physical activity).
Patients using oral or parenteral anticoagulation are not excluded provided they are on a stable dose of anticoagulant.
Patients with pre-existing hypertension should be on a stable antihypertensive regimen and have a blood pressure 150/100 mmHg at the time of enrollement.
Patients must not have known brain metastases because the study drug has not been adequately tested in this setting.

Sites / Locations

Abramson Cancer Center of the University of Pennsylvania

Outcomes

Primary Outcome Measures

Response Rate

We will use response as the primary efficacy marker to investigate the relationship between changes in autophagy markers and SUVs and the efficacy of treatment.

Secondary Outcome Measures

Progression-free survival

To evaluate the effects of baseline markers and treatment group on time to progression and survival, we will estimate propportional-hazards regression models. Time-to-event outcomes will be summarized with Kaplan-Meier survival curves.

Overall survival

Incidence of toxicity

Full Information

NCT ID

NCT01206530

First Posted

September 16, 2010

Last Updated

April 16, 2019

Sponsor

Abramson Cancer Center at Penn Medicine

1. Study Identification

Unique Protocol Identification Number

NCT01206530

Brief Title

FOLFOX/Bevacizumab/Hydroxychloroquine (HCQ) in Colorectal Cancer

Official Title

A Phase I/II Pharmacodynamic Study of Hydroxychloroquine in Combination With FOLFOX Plus Bevacizumab to Inhibit Autophagy in Colorectal Cancer

Study Type

Interventional

2. Study Status

Record Verification Date

April 2019

Overall Recruitment Status

Completed

Study Start Date

September 2010 (Actual)

Primary Completion Date

September 2017 (Actual)

Study Completion Date

September 2017 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Abramson Cancer Center at Penn Medicine

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

In this Phase I/II clinical trial, the investigators seek to pilot the addition of hydroxychloroquine (HCQ) to the standard front-line therapy of colorectal cancer, FOLFOX/bevacizumab. In toxicity terms, the investigators previous studies lead them to believe that a full dose (800mg) of HCQ will be well-tolerated in this setting. By starting at 600 mg, the investigators will ensure that the full dose is approached with an eye to safety, and if needed, the investigators will use the lower dose. Both doses achieve autophagy inhibition in our current studies.

Detailed Description

In this Phase I/II clinical trial, we seek to pilot the addition of HCQ to the standard front-line therapy of colorectal cancer, FOLFOX/bevacizumab. In toxicity terms, our previous studies lead us to believe that full dose (800mg) of HCQ will be welltolerated in this setting. By starting at 600 mg, we will ensure that the full dose is approached with an eye to safety, and if needed, we will use the lower dose. Both doses achieve autophagy inhibition in our current studies: for this reason, we are comfortable in including accrual to both dose-levels to the Phase II endpoints. If results are particularly striking, we will consider amending the study to expand accrual if the budget permits, but 25 patients permits an adequate assessment of activity of a novel regimen. The correlative endpoints of this trial are directed to the pharmacokinetics of HCQ, and pharmacodynamics of autophagy inhibition. We are currently constructing a population pharmacokinetic model of HCQ based on data from several ongoing trials, and the data from these patients will contribute to refining the model. We will analyze both measured and modelpredicted indices for their relationship to autophagy induction. Autophagy will be assessed as the accumulation of autophagocytic vesicles in the PMNs of treated patients, together with the induction of the expression of autophagyrelated proteins on western analysis, quantitated by densitometry. An exploratory correlative endpoint is the induction of metabolic changes as measured by 18FDG-PET. Our mechanistic hypothesis in this work is that the addition of HCQ will lead to a greater amount of cell death in the hypoxic regions of the tumor, that have increased as a consequence of bevacizumab treatment. We will document the rates of metabolic response as a consequence of treatment, as a therapeutic marker that may be related to the degree of autophagy inhibition. Finally, since we have demonistrated the key role of JNK1 in the induction of autophagy, we will analyze archival tumor materials to determine variability in this marker, as a baseline for potential future trials.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Rectal Cancer, Colon Cancer, Metastasis, Adenocarcinoma

Keywords

histologically documented, advanced, metastatic, adenocarcinoma, colon, rectum

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1, Phase 2

Enrollment

50 (Actual)

8. Arms, Groups, and Interventions

Intervention Type

Drug

Intervention Name(s)

Hydroxychloroquine

Intervention Description

Dose:600 or 800 mg Route:PO daily Treatment Administration: Daily

Intervention Type

Drug

Intervention Name(s)

Oxaliplatin

Intervention Description

Dose: 85mg/m2 Route: IV infusion over 2 hours Treatment Administration: Day 1

Intervention Type

Drug

Intervention Name(s)

Leucovorin

Intervention Description

Dose: 400mg/m2 Route IV infusion over 2 hours Treatment Administration: Day 1

Intervention Type

Drug

Intervention Name(s)

5-fluorouracil

Intervention Description

Dose: 400mg/m2 Route: IV bolus immediately following leucovorin Treatment Administration Day 1

Intervention Type

Drug

Intervention Name(s)

5-fluorouracil

Intervention Description

Dose: 2,400mg/m2 Route: IV continuous infusion over 46 hours immediately following bolus injection. Treatment Administration: Days 1-2

Intervention Type

Drug

Intervention Name(s)

Bevacizumab

Primary Outcome Measure Information:

Title

Response Rate

Description

We will use response as the primary efficacy marker to investigate the relationship between changes in autophagy markers and SUVs and the efficacy of treatment.

Secondary Outcome Measure Information:

Title

Progression-free survival

Description

Title

Overall survival

Description

Title

Incidence of toxicity

Description

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Patients must have histologically documented advanced or metastatic adenocarcinoma of the colon or rectum. Patients must have measurable disease as defined by the RECIST criteria as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded) as 20 mm with conventionaltechniques on either CT of MRI. Marker (CEA) elevation alone is insufficient for entry. Patients may have had prior adjuvant treatment of advanced colorectal cancer. The prior treatment regimen must not have included bevacizumab but may have included oxaliplatin and the last dose of chemotherapy must have been 6 months prior to study entry. Patients with prior radiotherapy are acceptable. It must be at least 2 weeks since administration of radiation therapy and all signs of toxicty must have abated. Patients must be 18 years or older. Patients must have an ECOG performance status of 0-1. The following required Initial Laboratory Values should be obtained within 4 weeks of the start of treatment: Granulocytes 1,500/ml, Platelet Count 100,000/ml, Creatinine 1.5 x upper limit of normal, Bilirubin 1.5 x upper limit of normal, AST 5 x upper limit of normal Urine Urine protein:creatinine ratio 1.0 at screening Patients must not be pregnant or lactating as chemotherapy is thought to present substantial risk to the fetus/infant. Patients must have a life expectancy of greater than three months. Patients must have the ability to understand and the willingness to sign a written informed consent document. Exclusion Criteria: Major sugical procedure, open biopsy, or significant traumatic injury within 28 days prior to Day 0, anticipation of need for major surgical procedure during the course of the study. Minor surgical procedures such as fine needle aspirations or core biopsies within 7 days prior to Day 0. Patients with serious nonhealing wounds, ulcers, or bone fractures. Patients with a history of abdominal fistula, gastrointestinal perforation or intra-abdominal abscess within 6 months prior to Day 0 Patients with a history of myocardial infarction, unstable angina, or cerebrovascular accident 6 months prior to registration. Patients with clinically significant peripheral vascular disease. Patients with New York Heart Association Class II or greater congestive heart failure (class II is defined as symptoms of fatigue, dyspnea or other symptoms with ordinary physical activity). Patients using oral or parenteral anticoagulation are not excluded provided they are on a stable dose of anticoagulant. Patients with pre-existing hypertension should be on a stable antihypertensive regimen and have a blood pressure 150/100 mmHg at the time of enrollement. Patients must not have known brain metastases because the study drug has not been adequately tested in this setting.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Peter J. O'Dwyer, MD

Organizational Affiliation

Abramson Cancer Center at Penn Medicine

Official's Role

Principal Investigator

Facility Information:

Facility Name

Abramson Cancer Center of the University of Pennsylvania

City

Philadelphia

State/Province

Pennsylvania

ZIP/Postal Code

19104

Country

United States

12. IPD Sharing Statement

Citations:

PubMed Identifier

33416261

Citation

Mendonca Gorgulho C, Krishnamurthy A, Lanzi A, Galon J, Housseau F, Kaneno R, Lotze MT. Gutting it Out: Developing Effective Immunotherapies for Patients With Colorectal Cancer. J Immunother. 2021 Feb-Mar 01;44(2):49-62. doi: 10.1097/CJI.0000000000000357.

Results Reference

derived

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FOLFOX/Bevacizumab/Hydroxychloroquine (HCQ) in Colorectal Cancer

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