Colorectal Adenocarcinoma
Conditions
Keywords
advanced stage colorectal adenocarcinoma
Brief summary
Establish the tolerability and safety of aimed dose of both quinacrine and capecitabine in combination to treat patients with advanced colorectal adenocarcinoma.
Detailed description
Because of the well published safety profiles of both quinacrine and capecitabine, the Phase I portion of our study will aim to determine the tolerability of both agents in combinations when used at established clinical doses. This portion of the study will more closely resemble a pilot study or feasibility study rather than a dose escalation Phase I trial. The objective is to determine toxicities and adverse reactions, not a maximally tolerated dose. The investigators hypothesize that there will be no toxic interactions at the pharmacokinetic or pharmacodynamic level, and want to know the feasibility of using quinacrine and capecitabine at their respective recommended single agent doses. Because capecitabine is already regarded as standard treatment for colorectal cancer, the investigators will begin the study with a full dose of capecitabine combined with a slightly lower dose of quinacrine. If the safety-interim analysis does not detect an excess of toxicity, then subsequent patients will be enrolled using the full dose of both drugs.
Interventions
DRUGQuinacrine and Capecitabine
The Phase I portion of the study will aim to determine the tolerability of both agents in combinations when used at established clinical doses. This portion of the study will more closely resemble a pilot study or feasibility study rather than a dose escalation.
Sponsors
Fox Chase Cancer Center
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patients much have histologically confirmed adenocarcinoma of the colon or rectum. * Patients must have measurable recurrence or metastases in the liver and/or lungs. * Patients must have prior chemotherapy for advanced colorectal cancer and have previously received both an oxaliplatin and an irinotecan based regimen. * Age \> 18 years. * Life expectancy greater than 4 weeks. * ECOG performance status \<3. * Patients must have normal organ and marrow function. * Patients must be able to swallow capsules. * Patients must be able to understand and willing to sign a written informed consent document. * Patients are included regardless of KRAS/BRAF status.
Exclusion criteria
* Patients who have had chemotherapy or radiotherapy within 4 weeks prior to entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier. * Patients may not be receiving any other investigational agent. * Patients with know brain metastases should be excluded from this clinical trial because they often develop progressive neurological dysfunction that would confound the evaluation of neurologic and other adverse events. * History of allergic reactions attributed to compounds of similar chemical or biologic composition to quinacrine, capecitabine or fluorouracil. * The concomitant use of quinacrine and primaquine is contraindicated. * 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 women are excluded from this study. * Patients with a baseline creatinine clearance of \< 50 mL/min. * Patients must be currently not treated with quinacrine or drugs related to quinacrine. * Patients who require anti-arrhythmic treatment with amiodarone or any drug with a quinidine-like effect on the heart or who have history of a malignant ventricular arrhythmia unless they have a functioning automatic implantable cardio defibrillator implanted. * Patients who have a history of noninfectious hepatitis or alcoholism. * Patients with a lifetime history of porphyria or psoriasis because it can exacerbate these conditions. * Patients with documented glucose-6-phosphate dehydrogenase deficiency. * Patients with a lifetime history of seizure disorder. * Patients with a lifetime history of dermatitis as an allergic/toxic reaction to any medication. * Patients with know dihydropyrimidine dehydrogenase deficiency.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Phase I - Number of Participants Who Experienced Dose Limiting Toxicities and Adverse Reactions | One year | Establish the tolerability of both agents in combination when used at established clinical doses. The objective is to determine toxicities and adverse reactions of patients in each group with different dose levels to find the maximum tolerated dose (MTD). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Phase II - Rate of Response | 2-3 years | Determine rate of response in patients receiving quinacrine in combination with capecitabine. Using Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1) complete response (CR) is a disappearance of all target lesions, partial response (PR) is at least 30% decrease in the sum of diameters of target lesions, and overall response is the number of patients who experience a complete response or partial response. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Phase II - Time to Progression (TTP) | 2-3 years | Determine time to progression from start of treatment in patients receiving quinacrine in combination with capecitabine. Using Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1), progression is defined as a 20% increase in sum of target lesions, with at least a 5 mm absolute increase. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Phase I Level -2 Phase I (Quinacrine and Capecitabine): The Phase I portion of the study will aim to determine the tolerability of both agents in combinations when used at established clinical doses. This portion of the study will more closely resemble a pilot study or feasibility study rather than a dose escalation.
Each group will have 1 to 6 patients enrolled in it. If the patients in a lower group do not have any significant side effects the next patient will start at the next group dose.
Group 1: capecitabine at a dose of 1000 mg/m\^2 twice per day (days 1-14), and quinacrine at a dose of 100 mg once per day (days 1-21) for a 21 day cycle | 1 |
| Phase I Level -1 Group 2: capecitabine at a dose of 1000 mg/m\^2 twice per day (days 1-14), quinacrine at a dose of 100 mg twice per day (days 1-21) for a 21 day cycle | 6 |
| Phase I Level 0 Group 3: capecitabine at a dose of 1000 mg/m\^2 twice per day (days 1-14), quinacrine at a dose of 200 mg twice a day (days 1-21) for a 21 day cycle | 3 |
| Phase II Phase II will use the treatment outlined in phase I, using the RP2D derived from Phase I.
Patients will receive capecitabine at a dose of 1000 mg/m\^2 twice per day (days 1-14), quinacrine at a dose of 100 mg twice per day (days 1-21) for a 21 day cycle | 7 |
| Total | 17 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 1 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Phase I Level -2 | Phase I Level -1 | Phase I Level 0 | Phase II | Total |
|---|---|---|---|---|---|
| Age, Continuous | 77 years | 56.5 years | 61 years | 61 years | 61 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 1 Participants | 5 Participants | 3 Participants | 6 Participants | 15 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Region of Enrollment United States | 1 participants | 6 participants | 3 participants | 7 participants | 17 participants |
| Sex: Female, Male Female | 0 Participants | 4 Participants | 1 Participants | 1 Participants | 6 Participants |
| Sex: Female, Male Male | 1 Participants | 2 Participants | 2 Participants | 6 Participants | 11 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 1 | 5 / 6 | 3 / 3 | 6 / 7 |
| other Total, other adverse events | 1 / 1 | 6 / 6 | 3 / 3 | 7 / 7 |
| serious Total, serious adverse events | 0 / 1 | 1 / 6 | 2 / 3 | 2 / 7 |
Outcome results
Primary
Phase I - Number of Participants Who Experienced Dose Limiting Toxicities and Adverse Reactions
Establish the tolerability of both agents in combination when used at established clinical doses. The objective is to determine toxicities and adverse reactions of patients in each group with different dose levels to find the maximum tolerated dose (MTD).
Time frame: One year
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase I Level -2 | Phase I - Number of Participants Who Experienced Dose Limiting Toxicities and Adverse Reactions | 0 Participants |
| Phase I Level -1 | Phase I - Number of Participants Who Experienced Dose Limiting Toxicities and Adverse Reactions | 0 Participants |
| Phase I Level 0 | Phase I - Number of Participants Who Experienced Dose Limiting Toxicities and Adverse Reactions | 3 Participants |
Secondary
Phase II - Rate of Response
Determine rate of response in patients receiving quinacrine in combination with capecitabine. Using Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1) complete response (CR) is a disappearance of all target lesions, partial response (PR) is at least 30% decrease in the sum of diameters of target lesions, and overall response is the number of patients who experience a complete response or partial response.
Time frame: 2-3 years
Population: Rate of response was analyzed for participants in phase II
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase I Level -2 | Phase II - Rate of Response | 0 Participants |
| Phase I Level -1 | Phase II - Rate of Response | 0 Participants |
| Phase I Level 0 | Phase II - Rate of Response | 0 Participants |
| Phase II | Phase II - Rate of Response | 1 Participants |
Other Pre-specified
Phase II - Time to Progression (TTP)
Determine time to progression from start of treatment in patients receiving quinacrine in combination with capecitabine. Using Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1), progression is defined as a 20% increase in sum of target lesions, with at least a 5 mm absolute increase.
Time frame: 2-3 years
Population: TTP was analyzed for participants enrolled in phase II
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase II | Phase II - Time to Progression (TTP) | 2.12 months |