KRAS Mutation-Related Tumors, Non-Small Cell Lung Cancer
Conditions
Brief summary
This study will evaluate using hydroxychloroquine (HCQ) along with binimetinib as an effective method for treating cancer. All patients will receive binimetinib at a standard dose approved for other cancers. The dose of HCQ will also be fixed based on ongoing phase I studies. Eligible subjects will have lung cancer that has a mutation in a key cancer gene called KRAS, and the cancer has spread to other parts of their body.
Interventions
DRUGBinimetinib Pill
Patients will be treated with B 45 mg two times daily and HCQ 400 mg twice daily beginning on day 1. The dose of HCQ is based on an ongoing Phase 1 trial, and may be modified in a future amendment prior to the first patient enrolled. Efforts will be made to ensure dose homogeneity throughout the trial. Treatment will be administered on an outpatient basis on a 28 day cycle
Patients will be treated with B 45 mg two times daily and HCQ 400 mg twice daily beginning on day 1. The dose of HCQ is based on an ongoing Phase 1 trial, and may be modified in a future amendment prior to the first patient enrolled. Efforts will be made to ensure dose homogeneity throughout the trial. Treatment will be administered on an outpatient basis on a 28 day cycle
Sponsors
Pfizer
Abramson Cancer Center at Penn Medicine
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
Yes
Inclusion criteria
1. Metastatic or incurable NSCLC 2. Presence of a non-synonymous mutation in KRAS 3. Patient must have received at least one prior systemic therapy for metastatic NSCLC or be intolerant/ineligible/refuse available therapies with known benefit 4. Ability and willingness to sign a written informed consent document 5. Age ≥18 years old 6. At least one measureable lesion according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 7. ECOG performance status 0-1 8. Adequate organ function 9. Women of childbearing potential must have a negative serum pregnancy test performed within 72hours of the first dose of study therapy. Subjects of reproductive potential must agree to use acceptable birth control methods (see Appendix B for childbearing potential). 10. Qtc \< 500 mSec on EKG 11. Must be able to swallow tablets 12. Must be willing to comply with protocol procedures (including completion of diaries and outcome measures
Exclusion criteria
1. Currently participating in or has participated in a study of an investigational agent or anticipated use of an investigational device within 4 weeks of the first dose of study treatment. 2. Untreated symptomatic central nervous system (CNS) metastases and/or carcinomatous meningitis. 3. Prior monoclonal antibody within 4 weeks prior to enrollment, or individuals who have not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier. 4. Known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin, non-invasive bladder tumors, or in situ cervical cancer 5. Active infection requiring systemic therapy with IV antibiotics 6. History or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator. 7. Known psychiatric or substance abuse disorders as documented in the chart that, in the opinion of the investigator, would interfere with cooperation with the requirements of the trial. 8. Pregnant or breastfeeding women 9. Anticipated receipt of any live vaccine within 30 days prior to the first dose of trial treatment. 10. Have a known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to study drug, or excipients or to dimethyl sulfoxide (DMSO). 11. Patients receiving cytochrome P450 enzyme-inducing anticonvulsant drugs (EIADs) (i.e. phenytoin, carbamazepine, Phenobarbital, primidone or oxcarbazepine) within 4 weeks of the start of the study treatment 12. Known Hepatitis B Virus (HBV), or Hepatitis C Virus (HCV) infection (subjects with laboratory evidence of cleared HBV and/or HCV will be permitted) 13. Patients with a previously documented retinal vein occlusion. 14. History or evidence of increased cardiovascular risk including any of the following: * Current clinically significant uncontrolled arrhythmias. Exception: Subjects with controlled atrial fibrillation for \> 30 days prior to randomization are eligible. * History of acute coronary syndromes (including myocardial infarction and unstable angina), coronary angioplasty, or stenting within 6 months prior to randomization. * Ejection fraction of ≤50% as measured by echocardiography or MUGA 15. Any other conditions judged by the investigator that would limit the evaluation of the subject
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate | 16 months | Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR. |
| Number of Patients With Adverse Events | 16 months | as assessed by CTCAE v5.0 |
Secondary
| Measure | Time frame |
|---|---|
| Progression-free Survival (PFS) | 16 months |
| Overall Survival (OS) | 16 months |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Binimetinib and Hydroxychloroquine Hydroxychloroquine (HCQ)in combination with Binimetinib (B). The starting dose for HCQ will be 400mg. Tablets of HCQ are available in 200 mg strength. HCQ will be administered in divided doses (every 12 hours) with or without food.
The starting dose of B is 45mg. B will be administered in divided doses (every 12 hours) with or without food
Binimetinib Pill: Patients will be treated with B 45 mg two times daily and HCQ 400 mg twice daily beginning on day 1. The dose of HCQ is based on an ongoing Phase 1 trial, and may be modified in a future amendment prior to the first patient enrolled. Efforts will be made to ensure dose homogeneity throughout the trial. Treatment will be administered on an outpatient basis on a 28 day cycle
Hydroxychloroquine Pill: Patients will be treated with B 45 mg two times daily and HCQ 400 mg twice daily beginning on day 1. The dose of HCQ is based on an ongoing Phase 1 trial, and may be modified in a future amendment prior to the first patient enrolled. Efforts will be made to ensure dose homogeneity throughout the trial. Treatment will be administered on an outpatient basis on a 28 day cycle | 9 |
| Total | 9 |
Baseline characteristics
| Characteristic | Binimetinib and Hydroxychloroquine |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 4 Participants |
| Age, Categorical Between 18 and 65 years | 5 Participants |
| Age, Continuous | 64 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 9 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 9 Participants |
| Region of Enrollment United States | 9 participants |
| Sex: Female, Male Female | 4 Participants |
| Sex: Female, Male Male | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 1 / 9 |
| other Total, other adverse events | 9 / 9 |
| serious Total, serious adverse events | 4 / 9 |
Outcome results
Primary
Number of Patients With Adverse Events
as assessed by CTCAE v5.0
Time frame: 16 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Single Arm: Hydroxychloroquine + Binimetinib | Number of Patients With Adverse Events | 9 Participants |
Primary
Objective Response Rate
Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.
Time frame: 16 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Single Arm: Hydroxychloroquine + Binimetinib | Objective Response Rate | 9 Participants |
Secondary
Overall Survival (OS)
Time frame: 16 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Single Arm: Hydroxychloroquine + Binimetinib | Overall Survival (OS) | 1 Participants |
Secondary
Progression-free Survival (PFS)
Time frame: 16 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Single Arm: Hydroxychloroquine + Binimetinib | Progression-free Survival (PFS) | 1 Participants |