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
Trial Snapshot
- Phase
- Phase 1
- Status
- Completed
- Enrollment
- 50
- Locations
- 1
- Primary Endpoint
- 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)
Study Overview
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.
Study Design
- Study Type
- Interventional
- Allocation
- Na
- Intervention Model
- Single Group
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- 18 Years to — (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
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
Exclusion Criteria
- Not provided
Arms & Interventions
Treatment (bortezomib, sorafenib tosylate)
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.
Intervention: 17-N-allylamino-17-demethoxygeldanamycin/bortezomib (Drug)
Treatment (bortezomib, sorafenib tosylate)
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.
Intervention: sorafenib tosylate (Drug)
Outcomes
Primary Outcomes
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)
Time Frame: Observed for at least 3 weeks at a given dose level combination
DLTs include: Hematologic: Grade 4 ANC for ≥5 days, Grade 4 anemia of any duration, or PLT \<25,000 of any duration; Renal: Serum creatinine ≥2 times baseline or \> 2x upper limit of normal if baseline levels normal; All other non-hematologic toxicities ≥grade 3 as per CTCAE v3.0 except fatigue; Any toxicities that caused dose delay of \> 2 weeks of the intended next dose. MTD is the dose level below the lowest dose that induces DLT in at least one-third of patients (2 of 6 patients).
Toxicity as assessed by CTCAE v3.0
Time Frame: Observed for at least 3 weeks at a given dose level combination
Non-hematologic toxicities will be evaluated via the ordinal CTC standard toxicity grading. Hematologic toxicity measures of thrombocytopenia, neutropenia, and leukopenia will be assessed using continuous variables as the outcome measures (primarily nadir) as well as categorization via Common Toxicity Criteria standard grading. Overall toxicity incidence as well as toxicity profiles by dose level, patient and tumor site will be explored and summarized. Frequency distributions, graphical techniques and other descriptive measures will form the basis of these analyses.
Antitumor activity as assessed by tumor measurement or evaluation of indicator lesion by computed tomography (CT) or magnetic resonance imaging (MRI)
Time Frame: 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
Effects of sorafenib on the disposition of bortezomib
Time Frame: From cohort II registration prior to each course
Up to 20 patients with hematologic malignancies will be treated at the MTD to evaluate markers of drug activity and pharmacokinetics of this combination.
Secondary Outcomes
- Best overall response as assessed using modified RECIST(Baseline until disease progression/recurrence)
- Tumor response as assessed by CT or MRI using modified Response Evaluation Criteria in Solid Tumors (RECIST)(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)
- Duration of overall response(From the time measurement criteria are met for CR/PR (whichever is first recorded) until the first date recurrent or progressive disease is documented)
- Duration of stable disease(From the start of the treatment until the criteria for progression are met)