Clinical trial NCT00303797: Sorafenib and Bortezomib in Treating Patients With Advanced Cancer
Official title: A Phase I Study of the Raf Kinase/VEGFR Inhibitor BAY 43-9006 in Combination With the Proteasome Inhibitor PS-341 in Patients With Advanced Malignancies
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Refractory Chronic Lymphocytic Leukemia
Refractory Multiple Myeloma
Stage III Multiple Myeloma
Stage IV Chronic Lymphocytic Leukemia
Unspecified Adult Solid Tumor, Protocol Specific
Lead sponsor: National Cancer Institute (NCI)
Sponsor class: NIH
First posted: 2006-03-17
Enrollment: 50
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 trial is studying the side effects and best dose of sorafenib and bortezomib in treating patients with advanced cancer. Sorafenib and bortezomib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Sorafenib may also stop the growth of cancer cells by blocking blood flow to the cancer

Detailed description: OBJECTIVES:

I. To determine the maximum tolerated dose (MTD) of sorafenib and bortezomib in patients with advanced malignancies.

II. To describe the toxicities associated with the combination of sorafenib and bortezomib.

III. To evaluate the therapeutic antitumor activity of the combination of sorafenib and bortezomib.

IV. To evaluate the effects of sorafenib on the disposition of bortezomib.

OUTLINE: This is a dose-escalation study. Patients are assigned to 1 of 2 groups according to disease type.

GROUP I (solid tumors-dose-escalation group): Patients receive oral sorafenib twice daily on days 1-21 and bortezomib IV over 3-5 seconds on days 1, 4, 8, and 11. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of sorafenib and bortezomib until the 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.

GROUP II (multiple myeloma or chronic lymphocytic leukemia-maximum tolerated dose \[MTD\] group): Patients receive oral sorafenib at the MTD twice daily on days 3-21 of course 1 and on days 1-21 of each subsequent course. Patients also receive bortezomib IV over 3-5 seconds at the MTD on days 1, 4, 8, and 11.

Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed for 3 months.

Eligibility criteria: Inclusion Criteria:

* Diagnosis of 1 of the following:

  * Cytologically or histologically proven unresectable solid tumor for which no curative treatment options exist (group I - dose-escalation phase)
  * Multiple myeloma or chronic lymphocytic leukemia requiring treatment (group II - maximum tolerated dose phase)

    * Failed ≥ 1 prior regimen
    * Non-secretory myeloma allowed
* No known standard therapy that is potentially curative or definitely capable of extending life expectancy exists
* Tumor amenable to serial sampling (group II)
* ECOG performance status 0-2
* Absolute neutrophil count ≥ 1,500/mm\^3
* Hemoglobin ≥ 9 g/dL
* Platelet count ≥ 100,000/mm\^3 (75,000/mm\^3 for patients with multiple myeloma \[group II\])
* Bilirubin ≤ 1.5 times upper limit of normal (ULN)
* AST ≤ 3 times ULN (5 times ULN if liver involvement)
* Creatinine ≤ 1.5 times ULN (2.5 times ULN for patients with multiple myeloma \[group II\])
* Life expectancy ≥ 12 weeks
* No uncontrolled infection
* No New York Heart Association class III or IV heart disease
* No uncontrolled hypertension, labile hypertension, or history of poor compliance with antihypertensive medication
* Not pregnant or nursing
* Negative pregnancy test
* Fertile patients must use effective contraception
* No sensory peripheral neuropathy of any etiology \> grade 1 or neuropathic pain of any etiology
* No active HIV infection requiring therapy
* No inability to swallow that would preclude use of oral medications
* No evidence of bleeding diathesis
* Medically capable and willing to provide biologic specimens as required (mandatory for patients in group II)
* Priorbortezomib allowed
* More than 3 weeks since prior chemotherapy (6 weeks for mitomycin C or nitrosoureas) and recovered
* More than 4 weeks since prior immunotherapy or biologic therapy
* More than 2 weeks since prior steroid therapy (group II only)
* No prior anti-vascular endothelial growth factor therapy
* More than 4 weeks since prior full-field radiotherapy (2 weeks for limited-field radiotherapy)
* No prior radiation to \> 25% of bone marrow
* More than 4 weeks since major surgery (e.g., laparotomy) (2 weeks for minor surgery)

  * Insertion of a vascular access device is not considered major or minor surgery
* No concurrent chemotherapy, immunotherapy, radiotherapy, or any ancillary other therapy considered investigational
* No concurrent prophylactic colony-stimulating factors
* No concurrent therapeutic anticoagulation

  * Concurrent prophylactic anticoagulation (i.e., low-dose warfarin) of venous or arterial access devices allowed provided requirements for PT, INR, or PTT are met
* No concurrent cytochrome P450 enzyme-inducing antiepileptic drugs (e.g., phenytoin, carbamazepine, and phenobarbital), rifampin, or Hypericum perforatum (St. John's Wort)
* No concurrent participation in any other study involving a pharmacologic agent (e.g., drugs, biologics, immunotherapy, or gene therapy), either for symptom control, or therapeutic intent

Primary outcomes:
measure: MTD as assessed by the number of patients with dose-limiting toxicity (DLT) using Common Terminology Criteria for Adverse Events version 3.0 (CTCAE v3.0)
timeFrame: Observed for at least 3 weeks at a given dose level combination
measure: Toxicity as assessed by CTCAE v3.0
timeFrame: Observed for at least 3 weeks at a given dose level combination
measure: Antitumor activity as assessed by tumor measurement or evaluation of indicator lesion by computed tomography (CT) or magnetic resonance imaging (MRI)
timeFrame: Baseline, prior to each course (every 3 weeks) during dose escalation, every 6 weeks for solid tumors, and confirmatory scans at least 4 weeks following initial documentation of objective response
measure: Effects of sorafenib on the disposition of bortezomib
timeFrame: From cohort II registration prior to each course
Secondary outcomes:
measure: Tumor response as assessed by CT or MRI using modified Response Evaluation Criteria in Solid Tumors (RECIST)
timeFrame: Baseline, every 3 weeks during dose escalation, every 6 weeks for solid tumors, and confirmatory scans at least 4 weeks following initial documentation of objective response
measure: Best overall response as assessed using modified RECIST
timeFrame: Baseline until disease progression/recurrence
measure: Duration of overall response
timeFrame: From the time measurement criteria are met for CR/PR (whichever is first recorded) until the first date recurrent or progressive disease is documented
measure: Duration of stable disease
timeFrame: From the start of the treatment until the criteria for progression are met
Other outcomes:
Locations:
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
Study officials:
affiliation: Mayo Clinic
name: Shaji Kumar
role: PRINCIPAL_INVESTIGATOR
References:
citation: Kumar SK, Jett J, Marks R, Richardson R, Quevedo F, Moynihan T, Croghan G, Markovic SN, Bible KC, Qin R, Tan A, Molina J, Kaufmann SH, Erlichman C, Adjei AA. Phase 1 study of sorafenib in combination with bortezomib in patients with advanced malignancies. Invest New Drugs. 2013 Oct;31(5):1201-6. doi: 10.1007/s10637-013-0004-2. Epub 2013 Jul 26.