Breast Cancer, Colon Cancer, Head and Neck Cancer, Hepatocellular Cancer, Kidney Cancer, Lung Cancer, Pancreatic Cancer, Sarcoma
Conditions
Keywords
Solid tumor malignancy, breast cancer, lung cancer, colon cancer, pancreatic cancer, head and neck cancer, kidney cancer, sarcoma, hepatocellular cancer
Brief summary
This is a Phase I study; dose escalating the combination of pazopanib when taken daily and ixabepilone when administered on day 1 of a 3 week treatment course.
Detailed description
Treatment with ixabepilone will be given at an assigned dose as a 3 hour intravenous infusion on day 1 of a 21 day cycle. Treatment with pazopanib will be given at an assigned dose by mouth once a day, beginning on day 1 and continuing daily. Disease assessment will be done every 2 cycles (6 weeks) with treatment continuing until disease progression, unacceptable toxicity or patient refusal.
Interventions
DRUGPazopanib
Escalating doses 400-800 mg by mouth once daily beginning day 1 and continuing.
DRUGIxabepilone
Escalating doses 25-32 mg/m2 by intravenous infusion on day 1 of each 21 day cycle
Sponsors
GlaxoSmithKline
Masonic Cancer Center, University of Minnesota
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Diagnosis of advanced non-hematologic solid tumor malignancy, including, but not limited to breast, lung, colon, pancreatic, head and neck, kidney or sarcoma that has failed or become intolerant to standard therapy and is no longer likely to respond to such therapy Effective with the August 2011 version of the protocol, enrollment is limited to squamous cell carcinoma of the head and neck (refer to section 1.4 for rationale). Note: Patients with a primary diagnosis of hepatocellular carcinoma will be eligible for enrollment into dose level 1 or 2 only, provided they met all other inclusion/
Exclusion criteria
- the maximum tolerated dose (MTD) for pazopanib monotherapy in patients with hepatocellular cancer was found to be 600 mg daily. * Measureable or evaluable disease per Response Evaluation Criteria in Solid Tumors (RECIST). * Prior systemic chemotherapy, immunotherapy, or biological therapy is allowed; however prior use of either pazopanib or ixabepilone alone or in combination is not allowed. * At least 14 days must have elapsed since 1) previous systemic therapy (28 days for bevacizumab) before the 1st dose of study drug, 2) last dose of radiation therapy or surgery (28 days for major surgery). * Patient must have recovered from the acute toxic effects of previous anti-cancer treatment prior to study enrollment. * Eastern Cooperative Oncology Group (ECOG) performance status of 0-1. * Adequate organ function within 14 days of enrollment defined as: * Absolute neutrophil count (ANC) \>1.5 x 10\^9/L * Hemoglobin \> or = 9 g/dL * Platelets \> or = 100 x 10\^9/L * Prothrombin time or international normalized ratio, and partial thromboplastin time (PTT) \< or = 1.2 x upper limit of normal (ULN) * Total bilirubin \< or = ULN * Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) \< or = 2.5 x ULN * Serum creatinine \< or = 1.5 mg/dL * Urine protein to Creatinine Ratio \< 1 * Total serum calcium \< 12.0 mg/dL * Men and women with child-bearing potential must adhere to protocol criteria to prevent conception during study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The Optimal Tolerated Regimen of Pazopanib and Ixabepilone When Used in Combination | Week 3 of each dose level | The optimal tolerated regimen is the regimen where ≤ 1 out of 6 patients experiences a dose limiting toxicity (DLT). DLT is defined as one of the following events occurring during cycle 1: grade 4 or greater treatment related hematologic toxicity for \> 7 days during the first cycle (21 days) of therapy; grade 3 or greater treatment related clinical non-hematological toxicity (excluding ≥ grade 3 nausea, vomiting, or diarrhea without maximal medical intervention and/or prophylaxis) during the first cycle (21 days) of therapy; or a delay of cycle 2 treatment start by more than 2 weeks due to incomplete hematologic recovery (ANC \> 1.5 x 109/L or platelets 100 x 109/L) or unresolved treatment related grade 3 or greater non-hematologic toxicity. |
| Number of Participants Who Experienced a Dose Limiting Toxicity (DLT) | Week 3 of each dose | A DLT was defined as one of the following events occurring during cycle 1: (1) grade 4 or greater treatment-related hematologic toxicity for \>7 days; (2) grade 3 or greater treatment-related clinical non-hematologic toxicity (excluding \>/= grade 3 nausea, vomiting, or diarrhea without maximal medical intervention and/or prophylaxis); or (3) delay of starting cycle 2 treatment by \>2 weeks due to incomplete hematologic recovery (absolute neutrophil count \> 1.5 X 10\^9/L or platelets \>100 X 10\^9/L) or unresolved treatment-related grade 3 or greater non-hematologic toxicity. Adverse events were classified according to Common Terminology Criteria for Adverse Events V 3.0 (CTCAE). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Treatment-Related Adverse Events | Up to 30 days post treatment | Includes all treatment-related adverse events experienced during and subsequent to Cycle 1. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Arm 1: Dose Level 1 Pazopanib 400mg - Ixabepilone 32mg/m2 | 9 |
| Arm 1: Dose Level 2 Pazopanib 400mg - Ixabepilone 40mg/m2 | 6 |
| Arm 1: Dose Level 3 Pazopanib 600mg - Ixabepilone 32 mg/m2 | 3 |
| Arm 1: Dose Level 4 Pazopanib 800mg - Ixabepilone 32 mg//m2 | 4 |
| Arm 2 Pazopanib 600mg - Ixabepilone 32 mg/m2. This is an additional cohort of head and neck cancer patients treated at the optimal tolerated regimen for the purpose of performing pharmacokinetics, confirm safety information and obtainadditional preliminary efficacy data in this patient population. | 9 |
| Total | 31 |
Baseline characteristics
| Characteristic | Arm 1: Dose Level 1 | Arm 1: Dose Level 2 | Arm 1: Dose Level 3 | Arm 1: Dose Level 4 | Arm 2 | Total |
|---|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 3 Participants | 1 Participants | 0 Participants | 1 Participants | 2 Participants | 7 Participants |
| Age, Categorical Between 18 and 65 years | 6 Participants | 5 Participants | 3 Participants | 3 Participants | 7 Participants | 24 Participants |
| Sex: Female, Male Female | 6 Participants | 1 Participants | 1 Participants | 1 Participants | 2 Participants | 11 Participants |
| Sex: Female, Male Male | 3 Participants | 5 Participants | 2 Participants | 3 Participants | 7 Participants | 20 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 9 / 9 | 6 / 6 | 12 / 12 | 4 / 4 |
| serious Total, serious adverse events | 4 / 9 | 3 / 6 | 7 / 12 | 3 / 4 |
Outcome results
Primary
Number of Participants Who Experienced a Dose Limiting Toxicity (DLT)
A DLT was defined as one of the following events occurring during cycle 1: (1) grade 4 or greater treatment-related hematologic toxicity for \>7 days; (2) grade 3 or greater treatment-related clinical non-hematologic toxicity (excluding \>/= grade 3 nausea, vomiting, or diarrhea without maximal medical intervention and/or prophylaxis); or (3) delay of starting cycle 2 treatment by \>2 weeks due to incomplete hematologic recovery (absolute neutrophil count \> 1.5 X 10\^9/L or platelets \>100 X 10\^9/L) or unresolved treatment-related grade 3 or greater non-hematologic toxicity. Adverse events were classified according to Common Terminology Criteria for Adverse Events V 3.0 (CTCAE).
Time frame: Week 3 of each dose
Population: 6 participants were included at Dose Level 1 to confirm safety after escalation to Dose level 2, but are grouped with the original 3 participants enrolled at Dose Level 1.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| All Arm 1 Participants | Number of Participants Who Experienced a Dose Limiting Toxicity (DLT) | 0 Participants |
| Arm 1: Dose Level 2 | Number of Participants Who Experienced a Dose Limiting Toxicity (DLT) | 3 Participants |
| Arm 1: Dose Level 3 | Number of Participants Who Experienced a Dose Limiting Toxicity (DLT) | 0 Participants |
| Arm 1: Dose Level 4 | Number of Participants Who Experienced a Dose Limiting Toxicity (DLT) | 1 Participants |
| Arm 2: Dose Level 3 | Number of Participants Who Experienced a Dose Limiting Toxicity (DLT) | 2 Participants |
Primary
The Optimal Tolerated Regimen of Pazopanib and Ixabepilone When Used in Combination
The optimal tolerated regimen is the regimen where ≤ 1 out of 6 patients experiences a dose limiting toxicity (DLT). DLT is defined as one of the following events occurring during cycle 1: grade 4 or greater treatment related hematologic toxicity for \> 7 days during the first cycle (21 days) of therapy; grade 3 or greater treatment related clinical non-hematological toxicity (excluding ≥ grade 3 nausea, vomiting, or diarrhea without maximal medical intervention and/or prophylaxis) during the first cycle (21 days) of therapy; or a delay of cycle 2 treatment start by more than 2 weeks due to incomplete hematologic recovery (ANC \> 1.5 x 109/L or platelets 100 x 109/L) or unresolved treatment related grade 3 or greater non-hematologic toxicity.
Time frame: Week 3 of each dose level
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| All Arm 1 Participants | The Optimal Tolerated Regimen of Pazopanib and Ixabepilone When Used in Combination | 3 Dose Level |
Secondary
Number of Participants With Treatment-Related Adverse Events
Includes all treatment-related adverse events experienced during and subsequent to Cycle 1.
Time frame: Up to 30 days post treatment
Population: Dose Level 3 includes participants from Arm 1: Dose Level 3 and Arm 2 combined.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| All Arm 1 Participants | Number of Participants With Treatment-Related Adverse Events | 9 Participants |
| Arm 1: Dose Level 2 | Number of Participants With Treatment-Related Adverse Events | 6 Participants |
| Arm 1: Dose Level 3 | Number of Participants With Treatment-Related Adverse Events | 12 Participants |
| Arm 1: Dose Level 4 | Number of Participants With Treatment-Related Adverse Events | 4 Participants |