A Study of the Hsp90 Inhibitor AUY922 Plus Capecitabine for the Treatment of Patients With Advanced Solid Tumors
Condition: Metastatic or Unresectable Solid Tumor Malignancy
MeSH terms: Neoplasms
Intervention: Capecitabine; Hsp90 Inhibitor AUY 922
Intervention description: Taken orally twice daily on Days 1 through 14 of 21 day cycle.; IV infusion over 60 minutes on Days 1, 8, and 15 of each 21 day cycle
Intervention MeSH terms: Capecitabine
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 23.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Solid tumor; Capecitabine; Hsp90 inhibitor AUY922

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.
    

Eligibility criteria:

        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.