Solid Tumor
Conditions
Keywords
Cancer, Surgery, Hydroxychloroquine
Brief summary
Baseline levels of PAR-4 secreted by normal cells are generally inadequate to cause massive apoptosis in cancer cells and drugs that bolster the secretion of PAR-4 would constitute an important therapeutic advance.The apoptosis sensitizing features of hydroxychloroquine enhance the anti-tumor effects of a broad range of cancer therapeutics. The investigators hypothesize that hydroxychloroquine will induce at least 2-fold increase in systemic (plasma) PAR-4 levels compared to pre-treatment plasma levels in patients with resectable solid tumors.
Interventions
DRUGHydroxychloroquine, 200mg twice dailiy
Hydroxychloroquine, 200mg twice daily (400mg/day total) was given to subjects for up to 14 days prior to surgery.
DRUGHydroxychloroquine, 400mg twice daily
Hydroxychloroquine, 400mg twice daily (800mg/day total) was given to subjects for up to 14 days prior to surgery.
Sponsors
Peng Wang, MD PhD
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patients must have a histologically confirmed solid tumor that is planned for surgical resection. * Age ≥18 years. * ECOG performance status ≤2 (Karnofsky ≥60%, see Appendix A). * Patients must be able to ingest oral medications. * Patients must have normal organ and marrow function as defined below: * absolute neutrophil count ≥1,500/mcL * platelets ≥100,000/mcL * total bilirubin Less than 1.5 x ULN * AST(SGOT)/ALT(SGPT) ≤2.5 × institutional upper limit of normal * Creatinine within normal institutional limits OR Creatinine clearance ≥60 mL/min/1.73 m2 for patients with creatinine levels above institutional normal. * Patients must be able to undergo surgical resection of their tumor as determined by the treating surgeon. * Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. * Ability to understand and the willingness to sign a written informed consent document.
Exclusion criteria
* Patients with metastatic cancer and/or cancer that is not amenable to surgery. * Patients with significant malabsorption as determined by the treating physician. * Patients who are receiving any other investigational agents. * Patients with known brain metastases are excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events. Patients with primary brain tumors amenable to surgery are allowed on this protocol. * History of allergic reactions attributed to compounds of similar chemical or biologic composition to hydroxychloroquine. * 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. * HIV-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with hydroxychloroquine. In addition, these patients are at increased risk of lethal infections when treated with marrow-suppressive therapy. * Patients that are on enzyme-inducing anti-epileptic medications
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Patients With Elevated Par-4 Levels | Baseline and day 14 | Number of patients with 2-fold change in Par-4 levels from baseline to day 14 |
| Optimal Biologic Dose of Hydroxychloroquine | Day 14 | Dose (mg twice daily) wherein 70% of patients exhibit a 2-fold increase in Par-4 levels with a dose-limiting toxicity of no more than 30%. |
Countries
United States
Participant flow
Recruitment details
This study was initiated July 2015 at the University of Kentucky and enrolled 10 adult patients with early stage solid malignancies.
Pre-assignment details
10 patients enrolled in this dose escalation study. In Period 1, three patients were assigned to receive 200mg HCQ twice daily. Based on toxicity and PAR-4 levels, in Period 2 the next four patients received 400mg HCQ twice daily. Following additional analysis, in Period 3 the final three patients received 200mg HCQ twice daily.
Participants by arm
| Arm | Count |
|---|---|
| Initial: Hydroxychloroquine 400mg HCQ Hydroxychloroquine 14 days
Hydroxychloroquine: Hydroxychloroquine (200mg twice per day; 400mg total) was given to subjects for up to 14 days prior to surgery. | 3 |
| Secondary: Hydroxychloroquine 800mg HCQ Hydroxychloroquine 14 days
Hydroxychloroquine: Hydroxychloroquine (400mg twice per day; 800mg total) was given to subjects for up to 14 days prior to surgery. | 4 |
| Tertiary: Hydroxychloroquine 400mg HCQ Hydroxychloroquine 14 days
Hydroxychloroquine: Hydroxychloroquine (200mg twice per day; 400mg total) was given to subjects for up to 14 days prior to surgery. | 3 |
| Total | 10 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Second Dose (400mg HCQ Twice Daily) | Protocol Violation | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | Initial: Hydroxychloroquine 400mg HCQ | Secondary: Hydroxychloroquine 800mg HCQ | Tertiary: Hydroxychloroquine 400mg HCQ | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 1 Participants | 1 Participants | 0 Participants | 2 Participants |
| Age, Categorical Between 18 and 65 years | 2 Participants | 3 Participants | 3 Participants | 8 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 3 Participants | 4 Participants | 3 Participants | 10 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 3 Participants | 4 Participants | 3 Participants | 10 Participants |
| Region of Enrollment United States | 3 participants | 4 participants | 3 participants | 10 participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Sex: Female, Male Male | 3 Participants | 4 Participants | 2 Participants | 9 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 3 | 0 / 4 | 1 / 3 |
| other Total, other adverse events | 1 / 3 | 2 / 4 | 1 / 3 |
| serious Total, serious adverse events | 0 / 3 | 0 / 4 | 0 / 3 |
Outcome results
Primary
Optimal Biologic Dose of Hydroxychloroquine
Dose (mg twice daily) wherein 70% of patients exhibit a 2-fold increase in Par-4 levels with a dose-limiting toxicity of no more than 30%.
Time frame: Day 14
Population: All patients
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Initial: Hydroxychloroquine 400mg HCQ | Optimal Biologic Dose of Hydroxychloroquine | 200 mg twice daily |
Primary
Patients With Elevated Par-4 Levels
Number of patients with 2-fold change in Par-4 levels from baseline to day 14
Time frame: Baseline and day 14
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Initial: Hydroxychloroquine 400mg HCQ | Patients With Elevated Par-4 Levels | 3 Participants |
| Secondary: Hydroxychloroquine 800mg HCQ | Patients With Elevated Par-4 Levels | 2 Participants |
| Tertiary: Hydroxychloroquine 400mg HCQ | Patients With Elevated Par-4 Levels | 1 Participants |