Study Evaluating Pantoprazole With Doxorubicin for Advanced Cancer Patients With Extension Cohort of Patients With Solid Tumours
This is a single-centre, open label, dose finding, phase I study to determine the recommended phase II dose (RP2D) for the combination of doxorubicin and pantoprazole in patients with advanced tumours and no standard treatment options. A minimum of 3 patients will be enrolled per dose level and intra-patient dose escalation is not permitted. Once the RP2D has been identified, six additional patients with metastatic solid tumours will be treated at the RP2D to confirm its tolerability.
Advanced Solid Tumours
Drug: pantoprazole sodium for injection
Drug: doxorubicin hydrochloride injection
|Study Design:||Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||A Phase I Study Evaluating the Proton Pump Inhibitor Pantoprazole in Combination With Doxorubicin for Advanced Cancer Patients With an Extension Cohort of Patients With Solid Tumours|
- Determination of recommended phase II dose (RP2D) of pantoprazole given with doxorubicin at 60mg/m2 [ Time Frame: Treatment until documented progression or up to 8 21-day cycles (4 cycles if prior anthracyclines received). All patients followed for late toxicities, every 3 months for 1 year or until all drug related toxicities are resolved/become unrelated. ] [ Designated as safety issue: Yes ]To determine the recommended phase II dose (RP2D) of pantoprazole given with doxorubicin at 60mg/m2 when administered to adult patients with advanced solid tumours.
- Characterize the safety and tolerability of the combination by determining dose-limiting toxicities (DLTs). Toxicities evaluated and graded according to the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. [ Time Frame: Treatment until documented progression or up to 8 21-day cycles (4 cycles if prior anthracyclines received). All patients followed for late toxicities, every 3 months for 1 year or until all drug related toxicities are resolved/become unrelated. ] [ Designated as safety issue: Yes ]Three or 6 patients will be treated per cohort for at least one cycle (21 days per cycle). If two patients experience DLTs, then accrual will stop at that level, and the next lower dose level in which six patients have been treated with no or only 1 DLT will be declared the RP2D. Once the RP2D has been identified, six additional patients will be treated at the RP2D to confirm its safety and tolerability. Patients will be assessed for toxicities using the overall safety profile as per National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0.
- Assess the preliminary anti-tumour activity of the doxorubicin/pantoprazole by combination in patients with advanced solid tumours, by evaluating tumour response rate. [ Time Frame: Radiologic evaluation (CT scan of chest, abdomen and pelvis) performed every 9 weeks ] [ Designated as safety issue: No ]Response Evaluation Criteria in Solid Tumours (RECIST) will be used to determine radiological tumour response for measurable disease and disease progression. Changes in only the largest diameter (unidimensional measurement) of the tumour lesions are used in the RECIST criteria. Any radiological change should be confirmed using a second follow-up scan, 6 or more weeks later. For response there must be no new lesions and no evidence of progression of non-measurable lesions.
- Evaluate the pharmacokinetics of doxorubicin and pantoprazole when given in combination by collecting venous blood samples at various timepoints throughout study drug administration. [ Time Frame: Blood samples just before and at the end of pantoprazole and doxorubicin administration, and at 1, 2, 4, 8, 24, 48 and 72 hours after (first or second) drug administration for evaluation of serum levels of doxorubicin and pantoprazole ] [ Designated as safety issue: No ]
- Evaluate (in selected patients with lesions amenable to biopsy) the influence of pantoprazole on distribution of doxorubicin in tumour tissue. Tumour tissue extracted after administration of doxorubicin/pantoprazole. [ Time Frame: Tumour biopsy within 24-48h after administration of doxorubicin (in consenting patients with disease amenable to biopsy) ] [ Designated as safety issue: No ]Two cores of tumour tissue will be extracted within 24-48 hours of administration of doxorubicin and pantoprazole;1 core will be fixed for routine pathological examination and the 2nd will be fresh frozen. The latter will be sectioned in the experimental pathology laboratory and will be stained with antibodies which recognize tumour blood vessels and regions of hypoxia. Distribution of doxorubicin (which is fluorescent) in relation to the blood vessels in tumours, and in relation to hypoxic regions, will then be quantified using immunohistochemistry at an advanced optical microscopy facility.
|Study Start Date:||July 2010|
|Estimated Study Completion Date:||September 2014|
|Estimated Primary Completion Date:||March 2014 (Final data collection date for primary outcome measure)|
|Experimental: Pantoprazole and doxorubicin||
Drug: pantoprazole sodium for injection
Single 3-weekly doses of pantoprazole using the following dose escalation scheme for successive groups of patients: 80, 160, 240 and 320mg i.v. of pantoprazole to be given every 3 weeks, 30-60 (±5) minutes prior to doxorubicin. Treatment will be repeated on Day 1 of a 21-day cycle until radiographic or symptomatic progression or unacceptable toxicity or a maximum of 4 cycles (for patients who have received prior anthracyclines), and up to 8 cycles (for those with no prior exposure to anthracyclines).
Other Names:Drug: doxorubicin hydrochloride injection
60 mg/m2, IV, scheduled on day 1 of every 3-week interval, 30-60 (±5) minutes after pantoprazole administration.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01163903
|Princess Margaret Hospital|
|Toronto, Ontario, Canada, M5G 2M9|
|Principal Investigator:||Ian F Tannock, MD, PhD, DSc||Princess Margaret Hospital, Canada|