Clinical trial NCT00112840: CCI-779 and Bevacizumab in Treating Patients With Metastatic or Unresectable Kidney Cancer
Official title: A Phase I/II Trial of CCI-779 and Bevacizumab in Stage IV Renal Cell Carcinoma
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Clear Cell Renal Cell Carcinoma
Recurrent Renal Cell Cancer
Stage IV Renal Cell Cancer
Lead sponsor: National Cancer Institute (NCI)
Sponsor class: NIH
First posted: 2005-06-03
Enrollment: 60
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: This phase I/II trial is studying the side effects and best dose of CCI-779 and bevacizumab and to see how well they work in treating patients with metastatic or unresectable kidney cancer. Drugs used in chemotherapy, such as CCI-779, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Monoclonal antibodies, such as bevacizumab, can block tumor growth in different ways. Some find tumor cells and kill them or carry tumor-killing substances to them. Others interfere with the ability of tumor cells to grow and spread. Bevacizumab may also stop the growth of kidney cancer by blocking blood flow to the tumor. Giving CCI-779 together with bevacizumab may kill more tumor cells.

Detailed description: PRIMARY OBJECTIVES:

I. To determine the maximally tolerated dose (MTD) and recommended dosing for the combination of CCI-779 and Bevacizumab in patients with metastatic renal cell cancer. (Phase I) II. To determine the proportion of patients with metastatic renal cell cancer who are progression free at 6 months. (Phase II)

SECONDARY OBJECTIVES:

I. To determine the toxicity of the combination of CCI 779 and Bevacizumab in patients with metastatic renal cell cancer. (Phase II) II. To determine the clinical response rate of CCI 779 and Bevacizumab in patients with metastatic renal cell cancer. (Phase II) III. To determine the time to progression (TTP), disease free survival, and overall survival of CCI 779 and Bevacizumab in patients with metastatic renal cell cancer. (Phase II)

TERTIARY OBJECTIVES:

I. To identify predictive molecular markers of response, both at the tumor level and in the plasma/serum level, in an exploratory manner.

II. To correlate blood markers of angiogenesis with clinical activity of the combination of CCI-779 and Bevacizumab.

OUTLINE: This is a multicenter, phase I dose-escalation study followed by a phase II study. Patients are stratified according to study phase (I vs II).

Phase I: Patients receive CCI-779 IV on days 1, 8, 15, and 22 and bevacizumab IV on days 1 and 15.

Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of CCI-779 and bevacizumab until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. Phase II: Patients receive CCI-779 and bevacizumab as in phase I at the MTD determined in phase I. After completion of study treatment, patients are followed every 3 months until disease progression and then every 6 months for up to 3 years after study entry.

Eligibility criteria: Inclusion Criteria:

* Histologically confirmed metastatic or unresectable renal cell cancer

  * Must have a component of conventional clear cell histology
  * The following histologies are excluded:

    * True papillary
    * Sarcomatoid features without any clear cell component
    * Chromophobe
    * Oncocytoma
    * Collecting duct tumors
    * Transitional cell carcinoma
* Measurable disease, defined as ≥ 1 lesion ≥ 2.0 cm in the longest diameter by conventional techniques OR ≥ 1.0 cm by spiral CT scan
* Tumor tissue (from primary tumor or metastases) available AND patient is willing to donate blood for research studies (phase II only)
* No CNS metastases by head CT scan or MRI
* Performance status - ECOG 0-2
* Absolute neutrophil count ≥ 1,500/mm\^3
* Platelet count ≥ 100,000/mm\^3
* Hemoglobin ≥ 9.0 g/dL
* No evidence of bleeding diathesis or coagulopathy
* No history of clinically significant bleeding or active bleeding
* Bilirubin ≤ 1.5 times upper limit of normal (ULN)
* Alkaline phosphatase ≤ 2.5 times ULN (5 times ULN if liver metastases are present)
* AST ≤ 2.5 times ULN (5 times ULN if liver metastases are present)
* PT/INR ≤ 1.5

  * Patients on full-dose warfarin or stable-dose low molecular weight heparin must have INR \> 1.5 but ≤ 3
* Creatinine ≤ 1.5 times ULN
* Urine protein ≤ 1+ by dipstick or urinalysis
* Urine protein \< 1,000 mg on a 24-hour urine collection
* No cerebrovascular accident within the past 6 months
* No peripheral vascular disease with claudication on \< 1 block
* No New York Heart Association class II-IV congestive heart failure
* No angina pectoris requiring nitrate therapy
* No myocardial infarction within the past 6 months
* No uncontrolled hypertension, defined as systolic blood pressure (BP) ≥ 160 mm Hg and/or diastolic BP ≥ 90 mm Hg despite medication
* No cardiac arrhythmias
* No other significant cardiovascular disease
* No ongoing hemoptysis
* Not pregnant or nursing
* Negative pregnancy test
* Fertile patients must use effective contraception during and for at least 3-4 months after study participation
* Fasting cholesterol ≤ 350 mg/dL
* Triglycerides ≤ 1.5 times ULN (may achieve using lipid lowering agents)
* No known hypersensitivity to recombinant human antibodies
* No significant traumatic injury within the past 4 weeks
* No serious or non-healing wound, ulcer, or bone fracture
* No abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within the past 4 weeks
* No pathological conditions that confer a high risk of bleeding (e.g., tumor involving major vessels or known varices)
* No diabetes
* No other currently active malignancy except nonmelanoma skin cancer

  * Patients are not considered to have a currently active malignancy if they have completed anticancer therapy AND are considered to be at \< 30% risk of relapse
* No other uncontrolled serious medical or psychiatric condition
* At least 4 weeks since prior biologic response modifiers for metastatic disease
* No prior bevacizumab or mTOR inhibitors
* At least 4 weeks since prior chemotherapy for metastatic disease
* Prior palliative radiotherapy to metastatic lesions allowed provided there is ≥ 1 measurable and/or evaluable lesion that has not been irradiated
* At least 4 weeks since prior and no concurrent radiotherapy
* Prior nephrectomy allowed
* More than 4 weeks since prior major surgery or open biopsy
* More than 1 week since prior core biopsy
* No concurrent major surgery
* At least 4 weeks (2 weeks for vascular endothelial growth factor \[VEGF\] receptor tyrosine kinase inhibitor \[RTKI\] therapy) since prior and no more than 2 therapies (phase II)

  * One of these therapies must have included a RTKI agent administered for a minimum of 4 weeks
* Concurrent full-dose warfarin or low molecular weight heparin allowed provided dose is stable AND INR requirements are met
* Concurrent zoledronate for bone metastases and/or hypercalcemia allowed provided therapy was initiated prior to study entry

Primary outcomes:
measure: Dose-limiting Toxicity (DLT) (Phase I)
timeFrame: Patients observed a minimum of 4 weeks (one full course). The maximum number of cycles observed was 16 cycles.
measure: Proportion of Progression-free Patients at 6 Months (Phase II)
timeFrame: 6 months after study entry
Secondary outcomes:
measure: Clinical Best Response Rate of CCI-779 and Bevacizumab in Patients With Metastatic Renal Cell (Phase II)
timeFrame: Up to 3 years from study registration
measure: Time to Progression (Phase II)
timeFrame: Up to 3 years from study registration
measure: Overall Survival (Phase I and II)
timeFrame: Up to 3 years from study registration
Other outcomes:
Locations:
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: Madison
country: United States
facility: University of Wisconsin Hospital and Clinics
state: Wisconsin
Study officials:
affiliation: Mayo Clinic
name: Jaime Merchan
role: PRINCIPAL_INVESTIGATOR
References: