Pancreatic Cancer
Conditions
Brief summary
The purpose of the study is to determine the optimal safe and tolerable dose of gemcitabine in combination with once daily or twice daily dose of PTK/ZK in patients with unresectable pancreatic cancer. The Phase II part of this study planned to determine the antitumor activity of this regimen and its effectiveness of preventing tumor growth and spread.
Interventions
DRUGVatalanib
Vatalanib 250 mg PO Q12 hours x 7 days, 8th day forward 500 mg PO Q12 hours
DRUGGemcitabine
850 mg/m2
Sponsors
Novartis
George Albert Fisher
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Histologically or cytologically confirmed adenocarcinoma of the pancreas * Unresectable (due to involvement of critical vasculature, adjacent organ invasion, or presence of metastasis) * If \> 5 years between the primary surgery and the development of metastatic disease, then separate histological or cytological confirmation of metastatic disease * Primary or metastatic lesion within 4 weeks prior to entry of study * WHO performance status of 0 to 2 * ≤ 18 years of age * Absolute Neutrophil Count (ANC) ≥ 1.5 x 10e9/L (\>= 1500/mm3) * Platelets (PLT) ≥ 100 x 10\^9/L (≥ 100,000/mm3) * Hemoglobin (Hgb) ≥ 9 g/dL * Serum creatinine ≤ 1.5 upper limit of normal (ULN) * Serum bilirubin ≤ 1.5 ULN * Aspartate aminotransferase (AST/SGOT) and alanine aminotransferase * (ALT/SGPT) ≤ 3.0 x ULN OR * ≤ 5 x ULN if liver metastases present * Proteinuria: * Negative for proteinuria based on dip stick reading OR * If dip stick reading is +1 result, then total urinary protein ≤ 500 mg and measured creatinine clearance (CrCl) ≥ 50 mL/min from a 24-hour urine collection * Life expectancy ≥ 12 weeks * Ability to give written informed consent
Exclusion criteria
* For the phase 1 portion of the study: prior gemcitabine will be therapy. * For the phase 2 portion of the study: any prior chemotherapy {except for low-dose 5-fluorouracil (5-FU)as a radiosensitizer\] * Radiotherapy (RT). The site of previous RT must have progressive disease if the only site of disease). * Prior full field radiotherapy ≤ 4 weeks prior to enrollment OR * Limited field radiotherapy ≤ 2 weeks prior to enrollment. Patients must have recovered from all therapy-related toxicities. * Prior biologic or immunotherapy ≤ 2 weeks prior to registration. * Prior therapy with anti-VEGF agents * History or presence of central nervous system (CNS) disease * Patients with a history of another primary malignancy ≤ 5 years (Exception: inactive basal or squamous cell carcinoma of the skin) * Major surgery ≤ 4 weeks prior to enrollment. (Exception: insertion of a vascular access device) * Minor surgery ≤ 2 weeks prior to enrollment. (Exception: insertion of a vascular access device) * Concurrent use of other investigational agents and patients who have received investigational drugs ≤ 4 weeks prior to enrollment. * Pregnant, or breast-feeding, not employing an effective method of birth control. * Pre-existing peripheral sensory neuropathy with functional impairment (≥ CTCAE grade 2 neuropathy) * Respiratory compromise due to pleural effusion or ascites (≥ CTCAE grade 2 dyspnea) * QTc \> 450 ms (male) or \> 470 ms (female) * Uncontrolled high blood pressure * History of labile hypertension * History of poor compliance with an antihypertensive regimen * Unstable angina pectoris * Symptomatic congestive heart failure * Myocardial infarction ≤ 6 months prior to registration / randomization * Serious uncontrolled cardiac arrhythmia * Uncontrolled diabetes * Active or uncontrolled infection * Interstitial pneumonia * Extensive and symptomatic interstitial fibrosis of the lung * Chronic renal disease * Acute or chronic liver disease * Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of vatalanib * Human immunodeficiency virus (HIV) infection (confirmed), if there is potential for interaction between vatalanib and any anti-HIV medication * HIV infection (confirmed) judged to increase subject risk due to the pharmacologic activity of vatalanib * Receiving warfarin sodium (Coumadin) or similar. Heparin is allowed. * Unwilling to or unable to comply with
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time-to-Treatment Failure (Intent-To-Treat Analysis) | 12 months | For the purposes of an Intent-to-Treat (ITT) analysis, Time-to-Treatment Failure (TTF) was defined as the time from treatment initiation to treatment discontinuation for any reason, including disease progression, treatment toxicity, patient preference, lost-to-follow-up, or death. Progression was defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time-to-Progression, Evaluable Patients | 12 months | Represents the evaluable subset of subjects that terminated from the study due to disease progression (endpoint). Does not include any other form of treatment failure, nor lost-to-follow-up. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Stage 1 Dose Exploration 0 - Gemcitabine 700 + Vatalanib 1250 Gemcitabine 700 mg/m2 + vatalanib 1250 mg daily
Vatalanib: Vatalanib 250 mg PO Q12 x 7 days, 8th day forward 500 mg PO Q12
Gemcitabine: 850 mg/m2 | 6 |
| Stage 1 Dose Exploration 1 - Gemcitabine 850 + Vatalanib 1250 Gemcitabine 850 mg/m2 + vatalanib 1250 mg
Vatalanib: Vatalanib 250 mg PO Q12 x 7 days, 8th day forward 500 mg PO Q12
Gemcitabine: 850 mg/m2 | 4 |
| Stage 1 Dose Explrtion2 - Gemcitabine850+Vatalanib 2x250/2x500 Gemcitabine 850 mg/m2 + vatalanib 250 mg Q12 hours x 1 week then 500 mg Q12 hours thereafter
Vatalanib: Vatalanib 250 mg PO Q12 x 7 days, 8th day forward 500 mg PO Q12
Gemcitabine: 850 mg/m2 | 6 |
| Stage 2 Dose Expansion - Gemcitabine850+Vatalanib 2x250/2x500 Gemcitabine 850 mg/m2 + vatalanib 500 mg twice daily
Vatalanib: Vatalanib 250 mg PO Q12 x 7 days, 8th day forward 500 mg PO Q12
Gemcitabine: 850 mg/m2 | 17 |
| Total | 33 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 3 | 1 | 4 | 2 |
| Overall Study | Lost to Follow-up | 0 | 0 | 1 | 2 |
| Overall Study | Physician Decision | 0 | 0 | 1 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Stage 1 Dose Exploration 0 - Gemcitabine 700 + Vatalanib 1250 | Stage 1 Dose Exploration 1 - Gemcitabine 850 + Vatalanib 1250 | Stage 1 Dose Explrtion2 - Gemcitabine850+Vatalanib 2x250/2x500 | Stage 2 Dose Expansion - Gemcitabine850+Vatalanib 2x250/2x500 | Total |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 1 Participants | 2 Participants | 4 Participants | 4 Participants | 11 Participants |
| Age, Categorical Between 18 and 65 years | 5 Participants | 2 Participants | 2 Participants | 13 Participants | 22 Participants |
| Age, Continuous | 55 years | 69 years | 70 years | 55 years | 58 years |
| Region of Enrollment United States | 6 participants | 4 participants | 6 participants | 17 participants | 33 participants |
| Sex: Female, Male Female | 4 Participants | 2 Participants | 2 Participants | 7 Participants | 15 Participants |
| Sex: Female, Male Male | 2 Participants | 2 Participants | 4 Participants | 10 Participants | 18 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 | 6 / 6 | 3 / 4 | 6 / 6 | 14 / 17 |
| serious Total, serious adverse events | 6 / 6 | 4 / 4 | 4 / 6 | 10 / 17 |
Outcome results
Primary
Time-to-Treatment Failure (Intent-To-Treat Analysis)
For the purposes of an Intent-to-Treat (ITT) analysis, Time-to-Treatment Failure (TTF) was defined as the time from treatment initiation to treatment discontinuation for any reason, including disease progression, treatment toxicity, patient preference, lost-to-follow-up, or death. Progression was defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0).
Time frame: 12 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Stage 1 Dose Exploration 0 - Gemcitabine 700 + Vatalanib 1250 | Time-to-Treatment Failure (Intent-To-Treat Analysis) | 4.9 months |
| Stage 1 Dose Exploration 1 - Gemcitabine 850 + Vatalanib 1250 | Time-to-Treatment Failure (Intent-To-Treat Analysis) | 2.7 months |
| Stage 1 Dose Explrtion2 - Gemcitabine850+Vatalanib 2x250/2x500 | Time-to-Treatment Failure (Intent-To-Treat Analysis) | 2.2 months |
| Stage 2 Dose Expansion - Gemcitabine850+Vatalanib 2x250/2x500 | Time-to-Treatment Failure (Intent-To-Treat Analysis) | 3.7 months |
Secondary
Time-to-Progression, Evaluable Patients
Represents the evaluable subset of subjects that terminated from the study due to disease progression (endpoint). Does not include any other form of treatment failure, nor lost-to-follow-up.
Time frame: 12 months
Population: Evaluable subset of subjects that terminated from the study due to disease progression (endpoint).~No participants were analyzed in the Stage 1 Dose Exploration 2 - Gemcitabine 850 + Vatalanib 2 x 250 / 2 x 500 group because no evaluable participants progressed within 12 months.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Stage 1 Dose Exploration 0 - Gemcitabine 700 + Vatalanib 1250 | Time-to-Progression, Evaluable Patients | 4.4 months |
| Stage 1 Dose Exploration 1 - Gemcitabine 850 + Vatalanib 1250 | Time-to-Progression, Evaluable Patients | 6.0 months |
| Stage 2 Dose Expansion - Gemcitabine850+Vatalanib 2x250/2x500 | Time-to-Progression, Evaluable Patients | 3.2 months |