Metastatic or Unresectable Solid Tumor Malignancy
Conditions
Keywords
Solid tumor, Capecitabine, Hsp90 inhibitor AUY922
Brief summary
The investigators propose this Phase I trial of the combination of AUY922 and capecitabine to determine the maximum tolerated dose (MTD) in patients with advanced solid tumors. This combination treatment has potential applicability in tumor types where capecitabine or fluorouracil is a treatment option, including colorectal and breast cancer.
Interventions
DRUGCapecitabine
Taken orally twice daily on Days 1 through 14 of 21 day cycle.
DRUGHsp90 Inhibitor AUY 922
IV infusion over 60 minutes on Days 1, 8, and 15 of each 21 day cycle
Sponsors
Novartis Pharmaceuticals
SCRI Development Innovations, LLC
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Histologically confirmed metastatic or unresectable solid tumor malignancy that is incurable and for which capecitabine is clinically appropriate. 2. Patient must be ≥4 weeks from administration of last dose of cancer therapy (including radiation therapy, biologic therapy, hormonal therapy or chemotherapy). Patients who received a small molecule targeted therapy as part of their first line treatment regimen must be ≥4 weeks or ≥5 half lives from administration of last dose whichever is shorter. The patient must have recovered from or come to a new chronic stable baseline from all treatment-related toxicities. 3. Eastern Collaborative Oncology Group (ECOG) performance status 0 to 1 (see Appendix A). 4. Life expectancy of ≥3 months. 5. At least one unidimensional measurable lesion definable by MRI or CT scan. Disease must be measurable per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 criteria (see Section 9). 6. Normal bone marrow function defined as: * Absolute neutrophil count (ANC) ≥1500/μL * Hemoglobin (Hgb) ≥9 g/dL * Platelets ≥100,000/μL 7. Adequate hepatic function defined as: * AST or ALT and alkaline phosphatase (ALP) must be ≤3 x ULN, or ≤5 x ULN in patients with liver metastases * Total bilirubin ≤1.5 x the institutional ULN 8. Renal function defined as: • Serum creatinine ≤1.5 x ULN or 24-hour creatinine clearance ≥40 mL/min 9. Normal electrolytes defined as: * Phosphorous ≥ LLN * Magnesium ≥ LLN 10. Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy test performed within 7 days prior to start of treatment. Women of childbearing potential must use effective birth control measures during treatment and during the 6 months following completion of study treatment. If a woman becomes pregnant or suspects she is pregnant while participating in this study, she must agree to inform her treating physician immediately. 11. Must be ≥18 years of age. 12. Patients must be accessible for treatment and follow-up. 13. Patients must be able to understand the investigational nature of this study and give written informed consent prior to study entry.
Exclusion criteria
1. Untreated CNS metastases. Patients with treated CNS metastases may be enrolled, provided the patient is asymptomatic, and the patient does not require antiepileptic drugs or steroids as treatment for the CNS metastases. 2. Treatment with therapeutic doses of coumarin-type anticoagulants (maximum daily dose of 1 mg allowed for port line patency permitted). 3. Impaired cardiac function with any one of the following: * History (or family history) of long QT syndrome * Mean QTc ≥450 msec on baseline ECG * History of clinically manifested ischemic heart disease (i.e. myocardial infarction and/or unstable angina) ≤6 months prior to study start * History of heart failure or left ventricular (LV) dysfunction (LVEF ≤45%) by MUGA or ECHO * Clinically significant ECG abnormalities including 1 or more of the following: left bundle branch block (LBBB), right bundle branch block (RBBB) with left anterior hemiblock (LAHB). ST segment elevation or depression \> 1mm, or 2nd (Mobitz II), or 3rd degree AV block. * History or presence of atrial fibrillation, atrial flutter or ventricular arrhythmias including ventricular tachycardia or Torsades de Pointes * Other clinically significant heart disease (e.g. congestive heart failure, uncontrolled hypertension, history of labile hypertension, or history of poor compliance with an antihypertensive regimen) * Clinically significant resting bradycardia (\< 50 beats per minute) * Patients who are currently receiving treatment with any medication which has a relative risk of prolonging the QTcF interval or inducing Torsades de Pointes and cannot be switched to an alternative drug or discontinued prior to commencing AUY922 (see Appendix D). * Obligate use of a cardiac pacemaker 4. Impairment of gastrointestinal function or gastrointestinal disease that in the opinion of the Investigator may significantly alter the absorption of study drugs (e.g., Crohn's disease, ulcerative disease, uncontrolled vomiting, diarrhea, or malabsorption syndrome). 5. Patients with known diagnosis of human immunodeficiency virus (HIV), hepatitis C virus, or acute or chronic hepatitis B infection. 6. Concurrent severe, intercurrent illness including, but not limited to, ongoing or active infection, or psychiatric illness/social situations that would limit compliance with study requirements. 7. Women who are pregnant (positive pregnancy test) or lactating. 8. Any condition that would prevent patient comprehension of the nature of, and risk associated with, the study, and the inability to comply with study and/or follow-up procedures.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Dose Determination | 18 months | To determine the maximum tolerated dose (MTD) of AUY922 plus capecitabine in patients with advanced solid tumors. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Drug Related Toxicities | 18 months | To evaluate the drug related toxicities associated with different doses of the drugs used in this regimen. |
| Preliminary Efficacy Assessment: Response Rate (RR) | 18 months | Response Rate (RR) is defined as the total number of patients with Complete Response (CR) or Partial Response (PR) as defined in RECIST v2. CR is defined as the dissappearance of all target lesions, disappearance of all non-target lesions and normalization of tumor markers. PR is defined as at least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum LD. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Dose Level 1 Hsp90 Inhibitor AUY922: 22mg/m2 IV days 1, 8, and 15 of 21-day cycles Capecitabine: 1000mg/m2 PO BID d 1-14 of 21-day cycles
Capecitabine: Taken orally twice daily on Days 1 through 14 of 21 day cycle.
Hsp90 Inhibitor AUY 922: IV infusion over 60 minutes on Days 1, 8, and 15 of each 21 day cycle | 3 |
| Dose Level 2 Hsp90 Inhibitor AUY922: 28mg/m2 IV days 1, 8, and 15 of 21-day cycles Capecitabine: 1000mg/m2 PO BID d 1-14 of 21-day cycles
Capecitabine: Taken orally twice daily on Days 1 through 14 of 21 day cycle.
Hsp90 Inhibitor AUY 922: IV infusion over 60 minutes on Days 1, 8, and 15 of each 21 day cycle | 3 |
| Dose Level 3 Hsp90 Inhibitor AUY922: 40mg/m2 IV days 1, 8, and 15 of 21-day cycles Capecitabine: 1000mg/m2 PO BID d 1-14 of 21-day cycles
Capecitabine: Taken orally twice daily on Days 1 through 14 of 21 day cycle.
Hsp90 Inhibitor AUY 922: IV infusion over 60 minutes on Days 1, 8, and 15 of each 21 day cycle | 3 |
| Dose Level 4 Hsp90 Inhibitor AUY922: 55mg/m2 IV days 1, 8, and 15 of 21-day cycles Capecitabine: 1000mg/m2 PO BID d 1-14 of 21-day cycles
Capecitabine: Taken orally twice daily on Days 1 through 14 of 21 day cycle.
Hsp90 Inhibitor AUY 922: IV infusion over 60 minutes on Days 1, 8, and 15 of each 21 day cycle | 5 |
| Dose Level 5 Hsp90 Inhibitor AUY922: 70mg/m2 IV days 1, 8, and 15 of 21-day cycles Capecitabine: 1000mg/m2 PO BID d 1-14 of 21-day cycles
Capecitabine: Taken orally twice daily on Days 1 through 14 of 21 day cycle.
Hsp90 Inhibitor AUY 922: IV infusion over 60 minutes on Days 1, 8, and 15 of each 21 day cycle | 3 |
| Dose Level 6 Hsp90 Inhibitor AUY922: 70mg/m2 IV days 1, 8, and 15 of 21-day cycles Capecitabine: 1250mg/m2 PO BID d 1-14 of 21-day cycles
Capecitabine: Taken orally twice daily on Days 1 through 14 of 21 day cycle.
Hsp90 Inhibitor AUY 922: IV infusion over 60 minutes on Days 1, 8, and 15 of each 21 day cycle | 6 |
| Total | 23 |
Baseline characteristics
| Characteristic | Dose Level 1 | Dose Level 2 | Dose Level 3 | Dose Level 4 | Dose Level 5 | Dose Level 6 | Total |
|---|---|---|---|---|---|---|---|
| Age, Continuous | 59 years | 51 years | 64 years | 60 years | 58 years | 65.5 years | 60 years |
| Region of Enrollment United States | 3 participants | 3 participants | 3 participants | 5 participants | 3 participants | 6 participants | 23 participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 1 Participants | 2 Participants | 1 Participants | 3 Participants | 7 Participants |
| Sex: Female, Male Male | 3 Participants | 3 Participants | 2 Participants | 3 Participants | 2 Participants | 3 Participants | 16 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 3 / 3 | 3 / 3 | 3 / 3 | 5 / 5 | 3 / 3 | 6 / 6 |
| serious Total, serious adverse events | 1 / 3 | 0 / 3 | 0 / 3 | 1 / 5 | 0 / 3 | 0 / 6 |
Outcome results
Primary
Dose Determination
To determine the maximum tolerated dose (MTD) of AUY922 plus capecitabine in patients with advanced solid tumors.
Time frame: 18 months
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| All Patients | Dose Determination | AUY922 dose | 70 mg/m^2 |
| All Patients | Dose Determination | Capecitabine dose | 1250 mg/m^2 |
Secondary
Drug Related Toxicities
To evaluate the drug related toxicities associated with different doses of the drugs used in this regimen.
Time frame: 18 months
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| All Patients | Drug Related Toxicities | Vision changes | 0 participants |
| All Patients | Drug Related Toxicities | Hand-foot syndrome | 1 participants |
| All Patients | Drug Related Toxicities | Diarrhea | 1 participants |
| All Patients | Drug Related Toxicities | Vomiting | 2 participants |
| All Patients | Drug Related Toxicities | Fatigue | 3 participants |
| All Patients | Drug Related Toxicities | Anorexia | 2 participants |
| All Patients | Drug Related Toxicities | Nausea | 2 participants |
| Dose Level 2 | Drug Related Toxicities | Diarrhea | 1 participants |
| Dose Level 2 | Drug Related Toxicities | Nausea | 2 participants |
| Dose Level 2 | Drug Related Toxicities | Fatigue | 0 participants |
| Dose Level 2 | Drug Related Toxicities | Hand-foot syndrome | 0 participants |
| Dose Level 2 | Drug Related Toxicities | Vision changes | 0 participants |
| Dose Level 2 | Drug Related Toxicities | Vomiting | 0 participants |
| Dose Level 2 | Drug Related Toxicities | Anorexia | 0 participants |
| Dose Level 3 | Drug Related Toxicities | Fatigue | 1 participants |
| Dose Level 3 | Drug Related Toxicities | Diarrhea | 2 participants |
| Dose Level 3 | Drug Related Toxicities | Vision changes | 1 participants |
| Dose Level 3 | Drug Related Toxicities | Hand-foot syndrome | 0 participants |
| Dose Level 3 | Drug Related Toxicities | Anorexia | 0 participants |
| Dose Level 3 | Drug Related Toxicities | Nausea | 1 participants |
| Dose Level 3 | Drug Related Toxicities | Vomiting | 1 participants |
| Dose Level 4 | Drug Related Toxicities | Nausea | 3 participants |
| Dose Level 4 | Drug Related Toxicities | Vision changes | 3 participants |
| Dose Level 4 | Drug Related Toxicities | Diarrhea | 3 participants |
| Dose Level 4 | Drug Related Toxicities | Fatigue | 1 participants |
| Dose Level 4 | Drug Related Toxicities | Hand-foot syndrome | 2 participants |
| Dose Level 4 | Drug Related Toxicities | Anorexia | 3 participants |
| Dose Level 4 | Drug Related Toxicities | Vomiting | 2 participants |
| Dose Level 5 | Drug Related Toxicities | Fatigue | 1 participants |
| Dose Level 5 | Drug Related Toxicities | Diarrhea | 3 participants |
| Dose Level 5 | Drug Related Toxicities | Vomiting | 2 participants |
| Dose Level 5 | Drug Related Toxicities | Vision changes | 3 participants |
| Dose Level 5 | Drug Related Toxicities | Anorexia | 1 participants |
| Dose Level 5 | Drug Related Toxicities | Nausea | 1 participants |
| Dose Level 5 | Drug Related Toxicities | Hand-foot syndrome | 1 participants |
| Dose Level 6 | Drug Related Toxicities | Vomiting | 0 participants |
| Dose Level 6 | Drug Related Toxicities | Hand-foot syndrome | 5 participants |
| Dose Level 6 | Drug Related Toxicities | Fatigue | 4 participants |
| Dose Level 6 | Drug Related Toxicities | Diarrhea | 4 participants |
| Dose Level 6 | Drug Related Toxicities | Anorexia | 2 participants |
| Dose Level 6 | Drug Related Toxicities | Vision changes | 6 participants |
| Dose Level 6 | Drug Related Toxicities | Nausea | 0 participants |
Secondary
Preliminary Efficacy Assessment: Response Rate (RR)
Response Rate (RR) is defined as the total number of patients with Complete Response (CR) or Partial Response (PR) as defined in RECIST v2. CR is defined as the dissappearance of all target lesions, disappearance of all non-target lesions and normalization of tumor markers. PR is defined as at least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum LD.
Time frame: 18 months
Population: Includes all patients evaluable for response. 4 patients were not evaluable: dose level 2 (1 pt), dose level 4 (2 pts), dose level 6 (1 pt).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| All Patients | Preliminary Efficacy Assessment: Response Rate (RR) | 1 participants |
| Dose Level 2 | Preliminary Efficacy Assessment: Response Rate (RR) | 0 participants |
| Dose Level 3 | Preliminary Efficacy Assessment: Response Rate (RR) | 0 participants |
| Dose Level 4 | Preliminary Efficacy Assessment: Response Rate (RR) | 2 participants |
| Dose Level 5 | Preliminary Efficacy Assessment: Response Rate (RR) | 1 participants |
| Dose Level 6 | Preliminary Efficacy Assessment: Response Rate (RR) | 0 participants |