Rectal CancerPhase 1/2NCT01206530
FOLFOX/Bevacizumab/Hydroxychloroquine (HCQ) in Colorectal Cancer
A Phase 1/2 study testing Hydroxychloroquine, Oxaliplatin and Leucovorin in people with Rectal Cancer and Colon Cancer, run by Abramson Cancer Center at Penn Medicine at 1 site in United States.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Rectal Cancer, Colon Cancer, Metastasis
- What is being tested?
- Hydroxychloroquine, Oxaliplatin and Leucovorin
- Type of treatment
- Injection or infusion
- How many people
- 50 participants
- Where
- 1 siteUnited States
- Study dates
- Sep 2010to Sep 2017
- Phase
- Phase 1/2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
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- 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.
Who cannot join
- 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).
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- 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.
Trial locations and contacts
1 site in 1 country.
United States1 site
Abramson Cancer Center of the University of Pennsylvania
Philadelphia, Pennsylvania, 19104
About this study
Official title: A Phase I/II Pharmacodynamic Study of Hydroxychloroquine in Combination With FOLFOX Plus Bevacizumab to Inhibit Autophagy in Colorectal Cancer
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.
Read the 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.
- Conditions
- Rectal Cancer, Colon Cancer, Metastasis, Adenocarcinoma
- Being tested
- Hydroxychloroquine, Oxaliplatin, Leucovorin, 5-fluorouracil, Bevacizumab
- Keywords
- histologically documented, advanced, metastatic, adenocarcinoma, colon, rectum
- Medical subject headings
- Rectal Neoplasms, Colonic Neoplasms, Neoplasm Metastasis, Adenocarcinoma
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Dose:600 or 800 mg Route:PO daily Treatment Administration: Daily
OxaliplatinDrug
Dose: 85mg/m2 Route: IV infusion over 2 hours Treatment Administration: Day 1
LeucovorinDrug
Dose: 400mg/m2 Route IV infusion over 2 hours Treatment Administration: Day 1
5-fluorouracilDrug
Dose: 400mg/m2 Route: IV bolus immediately following leucovorin Treatment Administration Day 1
5-fluorouracilDrug
Dose: 2,400mg/m2 Route: IV continuous infusion over 46 hours immediately following bolus injection.
Treatment Administration: Days 1-2
BevacizumabDrug
What is being measured
The primary outcome is the main question the study is designed to answer.
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 outcomes (3)
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
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.
Incidence of toxicity
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.
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted22 Sep 2010 (estimated)
- Study startSep 2010
- Primary completionSep 2017
- Study completionSep 2017
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Rectal CancerStudies of the same condition, open and under way.
- More trials run by Abramson Cancer Center at Penn MedicineThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1/2
- Primary purpose
- Treatment
- Enrolment
- 50 participants (actual)
Sponsor and investigators
- Lead sponsor
- Abramson Cancer Center at Penn Medicine
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Peter J. O'Dwyer, MD, Principal investigator, Abramson Cancer Center at Penn Medicine
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01206530
- Sponsor's protocol ID
- UPCC 07210
- Status last verified
- Apr 2019
- First submitted
- 16 Sep 2010
- Last updated
- 18 Apr 2019
- Results posted
- No
- Data monitoring committee
- Yes
Publications
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.
PubMed 33416261
Study at a glance
From the registry record, last updated by the sponsor on 18 Apr 2019. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Phase I/II Pharmacodynamic Study of Hydroxychloroquine in Combination With FOLFOX Plus Bevacizumab to Inhibit Autophagy in Colorectal Cancer
- ClinicalTrials.gov ID
- NCT01206530
- Acronym / sponsor ID
- UPCC 07210
- Conditions
- Rectal Cancer, Colon Cancer, Metastasis, Adenocarcinoma
- Keywords
- histologically documented, advanced, metastatic, adenocarcinoma, colon, rectum
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 50 participants (actual)
- Lead sponsor
- Abramson Cancer Center at Penn MedicineUniversity, hospital or other
- Study start
- Sep 2010 (actual)
- Primary completion
- Sep 2017 (actual)
- Study completion
- Sep 2017 (actual)
- First posted
- 22 Sep 2010 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (9 listed)
- 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.
Key exclusion criteria (9 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| HydroxychloroquineDose:600 or 800 mg Route:PO daily Treatment Administration: Daily | Drug | – |
| OxaliplatinDose: 85mg/m2 Route: IV infusion over 2 hours Treatment Administration: Day 1 | Drug | – |
| LeucovorinDose: 400mg/m2 Route IV infusion over 2 hours Treatment Administration: Day 1 | Drug | – |
| 5-fluorouracilDose: 400mg/m2 Route: IV bolus immediately following leucovorin Treatment Administration Day 1 | Drug | – |
| 5-fluorouracilDose: 2,400mg/m2 Route: IV continuous infusion over 46 hours immediately following bolus injection. Treatment Administration: Days 1-2 | Drug | – |
| Bevacizumab | Drug | – |
Primary outcome
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.
3 secondary outcomes
Progression-free survival
Overall survival
Incidence of toxicity
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 18 Apr 2019.
- Derived from this study: PubMed 33416261Mendonca 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.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Peter J. O'Dwyer, MD principal investigator
Abramson Cancer Center at Penn Medicine
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1/2 study testing Hydroxychloroquine, Oxaliplatin and Leucovorin in people with Rectal Cancer and Colon Cancer, run by Abramson Cancer Center at Penn Medicine at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 9 inclusion and 9 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 18 Apr 2019. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Response Rate. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT01206530, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 18 Apr 2019.