A Phase 1b/2 Study of BEZ235 in Patients With Advanced Renal Cell Carcinoma (RCC)
- Advanced renal cell carcinoma. Advanced disease is defined as unresectable, locally
recurrent disease or metastatic disease. This must by confirmed by MSKCC pathology
review with the following requirements:
- Phase 1b: Any histologic subtype of RCC.
- Phase 2: clear cell type RCC or predominant clear cell component.
Patients will be screened for prior systemic therapies:
- Phase 1b: Any prior therapy.
- Phase 2: Progression of disease on at least one prior treatment with an mTOR
inhibitor (such as everolimus, temsirolimus, ridaforolimus). Other prior systemic
therapies including VEGF directed therapy (e.g. sunitinib, sorafenib, bevacizumab)
and immunotherapy (e.g. IL-2, interferon-α) are also permitted. Evidence of
unidimensionally measurable disease per RECIST 1.1 (Eisenhauer, Therasse et al.
- Resolution of all acute toxic effects of prior systemic treatments, radiotherapy or
surgical procedures to NCI CTCAE Version 4.0 grade ≤1.
- Patient has an Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2,
which is not declining during the last 2 weeks.
- 18 years of age or older.
Adequate organ function as defined by the following criteria:
- Absolute neutrophil count (ANC) ≥1,000/μL
- Platelets ≥100,000/μL
- Hemoglobin ≥9.0 g/dL
- Serum calcium ≤12.0 mg/dL
- Serum creatinine ≤1.5 x upper limit of normal (ULN); if this is exceeded, estimated
creatinine clearance must be ≥ 30 ml/min
- Total serum bilirubin ≤ 1.5 x ULN (in patients with known Gilbert Syndrome, a total
bilirubin of ≤ 3 x ULN, with direct bilirubin ≤ 1.5 x ULN)
- Serum aspartate transaminase (AST) and serum alanine transaminase (ALT)
≤3 x ULN (≤5 x ULN in the setting of hepatic metastases)
- INR ≤ 2. (Anticoagulation with warfarin is contraindicated)
- Fasting plasma glucose (FPG) ≤ 140mg/dL
- HgbA1c ≤ 8%
- Fasting serum cholesterol ≤300 mg/dL, fasting triglycerides ≤ 2.5 x ULN. NOTE: In
case one or both of these thresholds are exceeded, the patient can only be included
after initiation of appropriate lipid lowering medication. Signed and dated informed
consent document indicating that the subject (or legally acceptable representative)
has been informed of all pertinent aspects of the trial prior to undergoing study
- Subject's willingness and ability to comply with scheduled visits, treatment plans,
laboratory tests, and other study procedures.
- Patients who have received prior treatment with a P13K inhibitor (Phase 2 portion
- Patients within 28 days post major surgery (e.g., intra-thoracic, intra-abdominal or
intra-pelvic) or significant traumatic injury.
- Patients who had radiation therapy within 28 days prior to start of study treatment
(palliative radiotherapy to bone lesions allowed if completed 2 weeks prior to study
- Patients who have received chemotherapy, immunotherapy or other investigational
agents ≤ 2 weeks prior to study treatment start.
Patients currently receiving medications known to be inducers or moderate / strong
inhibitors of CYP3A4 (see table 9.2 for a list) Patients must discontinue such medications
≥ 7 days prior to initiation of study treatment.
- Patients currently receiving medications with a significant risk to induce Torsades
- Patients who are currently receiving treatment with warfarin sodium (Coumadin®). If
treatment is discontinued or switched to an alternate anticoagulant prior to
enrollment, INR within ≤48h prior to study initiation has to return to ≤ 2 x ULN.
- Patients receiving chronic treatment with systemic corticosteroids or other
immunosuppressive agents (inhaled or topical steroids are allowed)
- Patients with evidence or history of central nervous system (CNS) metastases or
spinal cord compression, unless prior treatment with surgery or radiotherapy AND no
progression of CNS disease within 6 months prior to enrollment. Patients must not be
receiving chronic corticosteroid therapy for CNS metastases.
- Patients who have a history of severe medical conditions or other conditions that
could affect their participation in the study such as:
- symptomatic intrinsic lung disease requiring oxygen supplementation at baseline
- uncontrolled hypertension (i.e., SBP>180 mmHg or DBP >100mmHg)
- any active (acute or chronic) or uncontrolled infection/disorders that impair the
ability to evaluate the patient or for the patient to complete the study
- liver disease such as cirrhosis or decompensated liver disease.
- Impairment of gastrointestinal function that may impair absorption of BEZ235 (e.g.
ulcerative diseases, uncontrolled nausea/vomiting; diarrhea ≥ grade 2; malabsorption
syndromes after prior small-bowel resection)
- Immunocompromised patients and/or history of HIV seropositivity
Patients with prior or current cardiac problems including:
- History of unstable angina pectoris (at any time), symptomatic congestive heart
failure (NYHA III, IV) (at any time), serious uncontrolled cardiac arrhythmia (at any
time), myocardial infarction or cerebrovascular accidents ≤ 6 months prior to first
study treatment or history of left ventricular dysfunction
- reduced left ventricular ejection fraction (LVEF) of <50% on screening with
echocardiogram or multiple gates acquisition (MUGA) scan
- severe valvulopathies with documented compromise in cardiac function
- Any of the following on screening ECG:
- QTc interval > 480 msec (or family history of congenital QTc prolongation)
- Right bundle branch block + left anterior hemiblock (bifascicular block)
- Complete left bundle branch block
- Any conduction abnormality requiring pacemaker
- Symptomatic sinus bradycardia
- Any ventricular arrhythmia except for benign premature ventricular contractions
- Supraventricular and nodal arrhythmias requiring a pacemaker or not controlled with
- Symptomatic pericarditis
- Documented cardiomyopathy of any cause
- Female patients who are pregnant or breast feeding; pregnancy is defined as the state
of a female after conception and until the termination of gestation, confirmed by a
positive serum βhCG laboratory test (> 5 mIU/mL).
- Patients unwilling or unable to comply with adequate double barrier contraception
throughout the trial and for 12 weeks after the last dose of study drug (by both male
and female patients). This includes the following considerations:
- Hormonal contraceptives may be affected by cytochrome P450 interactions, and are
therefore considered neither indicated nor effective.
- Adequate barrier methods of contraception include: diaphragm, condom (by the
partner), intrauterine device (copper), sponge or spermicide.
- Women are considered post-menopausal and not of child bearing potential if they have
had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical
profile (e.g., age appropriate, history of vasomotor symptoms) or six months of
spontaneous amenorrhea with serum FSH levels > 40 mIU/mL [for US only: and estradiol
< 20 pg/mL] or have had surgical bilateral oophorectomy (with or without
hysterectomy) at least six weeks ago. In the case of oophorectomy alone, only when
the reproductive status of the woman has been confirmed by follow up hormone level
assessment is she considered not of child bearing potential
- Patients who have a history of another primary malignancy and are off treatment for ≤
3 years, with the exception of non-melanoma skin cancer and carcinoma in situ of the
- Patients who have received attenuated live vaccines within one week of study entry.
Examples of live vaccines include intranasal influenza, measles, mumps, rubella, oral
polio, BCG, yellow fever, varicella and TY21a typhoid vaccines.
- Known intolerance to the study drug (or any of the excipients), and/or known
hypersensitivity to PI3K inhibitor (eg. GDC-0980), and/or known hypersensitivity to
rapamycins (eg. Sirolimus, everolimus, temsirolimus) or any of the excipients.