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Hydroxychloroquine in Previously Treated Patients With Metastatic Pancreatic Cancer

Primary Purpose

Pancreatic Cancer

Status

Completed

Phase

Phase 2

Locations

United States

Study Type

Interventional

Intervention

Hydroxychloroquine

About this trial

This is an interventional treatment trial for Pancreatic Cancer focused on measuring metastatic pancreatic cancer, hydroxychloroquine

Eligibility Criteria

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

Inclusion Criteria:

Histologically confirmed unresectable pancreatic adenocarcinoma that is metastatic to distant sites
Measurable disease, defined as at least one lesion that can accurately be measured in at least one dimension
Patients must have been treated with one or two previous lines of chemotherapy for metastatic disease with documented tumor progression or intolerance due to toxicity
Minimum of two weeks since any major surgery, completion of radiation, or completion of all prior systemic anticancer therapy
18 years of age or older
Life expectancy of greater than 12 weeks
ECOG performance status of 0, 1 or 2
Normal organ and marrow function as outlined in the protocol
Patients must be able to swallow pills
Women of child-bearing potential and men must agree to use adequate contraception prior to study entry and for the duration of study participation.

Exclusion Criteria:

Participants who have had chemotherapy or radiotherapy within 2 weeks prior to entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier.
More than two previous chemotherapy regimens for the treatment of metastatic pancreatic cancer
Uncontrolled brain or leptomeningeal metastases
History of macular degeneration, visual field changes, retinal disease, or cataracts that would interfere with funduscopic eye examinations
History of allergic reactions attributed to compounds of similar chemical or biologic composition to hydroxychloroquine
Previous treatment with chloroquine or hydroxychloroquine for other indications, such as rheumatoid arthritis, SLE or malaria prophylaxis
Prior treatment with any investigational drug within the preceding 4 weeks
Impairment of gastrointestinal function or gastrointestinal disease that may significantly alter absorption of hydroxychloroquine. Patients who have undergone a Whipple procedure for localized pancreatic cancer are not excluded from enrollment
History of non-compliance to medical regimens
Known diagnosis of glucose-6-phosphate deficiency, porphyria or psoriasis
Penicillamine use for Wilson's disease or any other indication
Uncontrolled intercurrent illness including but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
Pregnant or breastfeeding women
Individuals with a history of a different malignancy are ineligible except for the following circumstances. Individuals with a history of other malignancies are eligible if they have been disease-free for at least 3-years and are deemed by the investigator to be at low risk for recurrence of that malignancy. Individuals with the following cancers are eligible if diagnosed and treated within the past three years: cervical cancer in situ, and basal cell or squamous cell carcinoma
HIV-positive individuals on combination antiretroviral therapy

Sites / Locations

Dana-Farber Cancer Institute
Massachusetts General Hospital

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Arm Label

Hydroxychloroquine 400 mg b.i.d.

Hydroxychloroquine 600 mg b.i.d.

Arm Description

Patients received 400 mg hydroxychloroquine orally twice per day. Cycle duration was 4 weeks. Patients remained on treatment indefinitely without the occurrence of disease progression, unacceptable adverse events, patient withdrawal, or discontinuation per MD decision.

Patients received 600 mg hydroxychloroquine orally twice per day. Cycle duration was 4 weeks. Patients remained on treatment indefinitely without the occurrence of disease progression, unacceptable adverse events, patient withdrawal, or discontinuation per MD decision.

Outcomes

Primary Outcome Measures

2-month Progression-Free Survival Rate

2-month progression-free survival rate was defined as the percentage of patients absent progression (PD) or death before 2 months. Patients were considered to have experienced PD if they demonstrated either clinical deterioration resulting in withdrawal or PD per RECIST 1.0 criteria: At least a 20% increase in the sum of longest diameter (LD) of target lesions taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions. PD for the evaluation of non-target lesions is the appearance of one or more new lesions and/or unequivocal progression of non-target lesions.

Secondary Outcome Measures

Biochemical Response Rate

Biochemical response rate was defined as the percentage of patients achieving on treatment a decrease in serum CA 19-9 by > 30% from baseline.

Tumor Response Rate

Tumor response rate is the percentage of patients achieving complete or partial response on treatment based on RECIST 1.0 criteria. For target lesions, complete response (CR) is disappearance of all target lesions and partial response (PR) is at least a 30% decrease in the sum of longest diameter (LD) of target lesions, taking as reference baseline sum LD. CR for the evaluation of non-target lesions is the disappearance of non-target lesions and normalization of tumor marker level. Appearance of one or more new lesions is classified as progression of non-target lesions. CR or PR confirmation is required >/= 4 weeks.

Overall Survival

Overall survival estimated using Kaplan-Meier (KM) methods is defined as the time from study entry to death or date last known alive.

Progression-Free Survival

Progression-free survival based on the Kaplan-Meier method is defined as the duration of time from study entry to time of objective progression on CT scan or the time of death for patients with clinical deterioration resulting in withdrawal from the trial. Per RECIST 1.0 criteria: progressive disease (PD) is at least a 20% increase in the sum of longest diameter (LD) of target lesions taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions. PD for the evaluation of non-target lesions is the appearance of one or more new lesions and/or unequivocal progression of non-target lesions. Patients without an event were censored at date of last disease evaluation.

Grade 4-5 Treatment-Related Toxicity

All grade 4-5 adverse events with treatment attribution of possibly, probably or definite based on CTCAEv3 as reported on case report forms.

Full Information

NCT ID

NCT01273805

First Posted

January 7, 2011

Last Updated

May 19, 2017

Sponsor

Dana-Farber Cancer Institute

Collaborators

Brigham and Women's Hospital, Massachusetts General Hospital

1. Study Identification

Unique Protocol Identification Number

NCT01273805

Brief Title

Hydroxychloroquine in Previously Treated Patients With Metastatic Pancreatic Cancer

Official Title

Phase II Study of Hydroxychloroquine in Previously Treated Patients With Metastatic Pancreatic Cancer

Study Type

Interventional

2. Study Status

Record Verification Date

May 2017

Overall Recruitment Status

Completed

Study Start Date

January 2011 (Actual)

Primary Completion Date

January 2013 (Actual)

Study Completion Date

February 2014 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

Dana-Farber Cancer Institute

Collaborators

Brigham and Women's Hospital, Massachusetts General Hospital

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

Hydroxychloroquine is approved for the treatment of non-cancerous illnesses such as rheumatoid arthritis and systemic lupus erythematous. Researchers in the laboratory have tested tumors from patients with pancreatic cancer and have discovered that they have certain pathways inside the cells that promote growth and survival of the tumor. Hydroxychloroquine may inactivate these pathways and results in the death of pancreatic cancer cells.

Detailed Description

Primary Objective To determine the efficacy of single-agent hydroxychloroquine in patients with metastatic pancreatic cancer previously treated with one or two prior chemotherapy regimens as measured by progression-free survival at two months Secondary Objectives To assess tumor response rate, biochemical response rate (i.e. decrease in serum CA19-9 by > 30%), and overall survival Translational/Exploratory Objectives To investigate predictors of response to anti-autophagy therapy with hydroxychloroquine To explore the kinetics of in vivo autophagy inhibition using peripheral blood WBCs to monitor autophagic activity among patients receiving hydroxychloroquine

6. Conditions and Keywords

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

Pancreatic Cancer

Keywords

metastatic pancreatic cancer, hydroxychloroquine

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Single Group Assignment

Model Description

There were 2 arms in this study because the study was amended to evaluate a second cohort of patients treated at a higher dose using the same two-stage statistical design.

Masking

None (Open Label)

Allocation

Non-Randomized

Enrollment

20 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Hydroxychloroquine 400 mg b.i.d.

Arm Type

Experimental

Arm Description

Arm Title

Hydroxychloroquine 600 mg b.i.d.

Arm Type

Experimental

Arm Description

Intervention Type

Drug

Intervention Name(s)

Hydroxychloroquine

Other Intervention Name(s)

Plaquenil

Primary Outcome Measure Information:

Title

2-month Progression-Free Survival Rate

Description

Time Frame

Disease was evaluated radiologically at baseline and at the first restaging at 2 months.

Secondary Outcome Measure Information:

Title

Biochemical Response Rate

Description

Biochemical response rate was defined as the percentage of patients achieving on treatment a decrease in serum CA 19-9 by > 30% from baseline.

Time Frame

Disease was evaluated radiologically at baseline and every 2 months on treatment. Median duration of treatment for this study cohort was 34 days.

Title

Tumor Response Rate

Description

Time Frame

Disease was evaluated radiologically at baseline and every 2 months on treatment. Median duration of treatment for this study cohort was 34 days.

Title

Overall Survival

Description

Overall survival estimated using Kaplan-Meier (KM) methods is defined as the time from study entry to death or date last known alive.

Time Frame

All patients were followed until death. Median survival follow-up in this study cohort was 60 days (95% CI: 40-184).

Title

Progression-Free Survival

Description

Time Frame

Disease was evaluated radiologically at baseline and every 2 months on treatment. Median PFS follow-up in this study cohort was 46.5 days (95% CI 33-61).

Title

Grade 4-5 Treatment-Related Toxicity

Description

All grade 4-5 adverse events with treatment attribution of possibly, probably or definite based on CTCAEv3 as reported on case report forms.

Time Frame

Adverse events were assessed each cycle throughout treatment. Participants were followed for the duration of treatment, an average of 34 days for this study population.

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Histologically confirmed unresectable pancreatic adenocarcinoma that is metastatic to distant sites Measurable disease, defined as at least one lesion that can accurately be measured in at least one dimension Patients must have been treated with one or two previous lines of chemotherapy for metastatic disease with documented tumor progression or intolerance due to toxicity Minimum of two weeks since any major surgery, completion of radiation, or completion of all prior systemic anticancer therapy 18 years of age or older Life expectancy of greater than 12 weeks ECOG performance status of 0, 1 or 2 Normal organ and marrow function as outlined in the protocol Patients must be able to swallow pills Women of child-bearing potential and men must agree to use adequate contraception prior to study entry and for the duration of study participation. Exclusion Criteria: Participants who have had chemotherapy or radiotherapy within 2 weeks prior to entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier. More than two previous chemotherapy regimens for the treatment of metastatic pancreatic cancer Uncontrolled brain or leptomeningeal metastases History of macular degeneration, visual field changes, retinal disease, or cataracts that would interfere with funduscopic eye examinations History of allergic reactions attributed to compounds of similar chemical or biologic composition to hydroxychloroquine Previous treatment with chloroquine or hydroxychloroquine for other indications, such as rheumatoid arthritis, SLE or malaria prophylaxis Prior treatment with any investigational drug within the preceding 4 weeks Impairment of gastrointestinal function or gastrointestinal disease that may significantly alter absorption of hydroxychloroquine. Patients who have undergone a Whipple procedure for localized pancreatic cancer are not excluded from enrollment History of non-compliance to medical regimens Known diagnosis of glucose-6-phosphate deficiency, porphyria or psoriasis Penicillamine use for Wilson's disease or any other indication Uncontrolled intercurrent illness including but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements Pregnant or breastfeeding women Individuals with a history of a different malignancy are ineligible except for the following circumstances. Individuals with a history of other malignancies are eligible if they have been disease-free for at least 3-years and are deemed by the investigator to be at low risk for recurrence of that malignancy. Individuals with the following cancers are eligible if diagnosed and treated within the past three years: cervical cancer in situ, and basal cell or squamous cell carcinoma HIV-positive individuals on combination antiretroviral therapy

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Brian Wolpin, MD, MPH

Organizational Affiliation

Dana-Farber Cancer Institute

Official's Role

Principal Investigator

Facility Information:

Facility Name

Dana-Farber Cancer Institute

City

Boston

State/Province

Massachusetts

ZIP/Postal Code

02115

Country

United States

Facility Name

Massachusetts General Hospital

City

Boston

State/Province

Massachusetts

ZIP/Postal Code

02214

Country

United States

12. IPD Sharing Statement

Plan to Share IPD

Citations:

PubMed Identifier

24821822

Citation

Wolpin BM, Rubinson DA, Wang X, Chan JA, Cleary JM, Enzinger PC, Fuchs CS, McCleary NJ, Meyerhardt JA, Ng K, Schrag D, Sikora AL, Spicer BA, Killion L, Mamon H, Kimmelman AC. Phase II and pharmacodynamic study of autophagy inhibition using hydroxychloroquine in patients with metastatic pancreatic adenocarcinoma. Oncologist. 2014 Jun;19(6):637-8. doi: 10.1634/theoncologist.2014-0086. Epub 2014 May 12.

Results Reference

result

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Hydroxychloroquine in Previously Treated Patients With Metastatic Pancreatic Cancer

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