ABC-04 a Study of Cisplatin, Gemcitabine and Selumetinib in Patients With Advanced Biliary Tract Cancer

Sponsor

University College, London (Other)

Overall Status

Completed

CT.gov ID

NCT01242605

Collaborator

AstraZeneca (Industry)

Enrollment

Locations

Arm

Duration (Months)

4.3

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The objective of this study is to establish the recommended dose of selumetinib, a novel MEK inhibitor for use in combination with gemcitabine and cisplatin.

Condition or Disease	Intervention/Treatment	Phase
Biliary Tract Neoplasms Cholangiocarcinoma Gallbladder Neoplasms	Drug: selumetinib Drug: gemcitabine Drug: cisplatin	Phase 1

Detailed Description

This trial aims to evaluate the safety and tolerability of selumetinib in combination with CisGem and to establish the recommended dose to take into phase II studies. Pharmacokinetic and pharmacodynamic endpoints will be assessed and preliminary efficacy data will also be collected.

Patients with Advanced Biliary tract Cancer will receive CisGem regimen and selumetinib. A dose de-escalation scheme will be employed to determine the recommended phase II dose of selumetinib.

Patients will be recruited in cohorts of three and assessed for dose limiting toxicity (DLT) during the first cycle of treatment. Depending on the number of DLTs observed, the cohort may be expanded, the next cohort may be enrolled at a lower dose or the dose may be declared the recommended dose. Patients will receive up to eight cycles of CisGem and may continue to receive selumetinib until progression of disease.

Study Design

Study Type:

Interventional

Actual Enrollment :

13 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

ABC-04 a Phase 1B Study of Cisplatin, Gemcitabine and Selumetinib in Patients With Advanced Biliary Tract Cancer

Study Start Date :

Feb 1, 2012

Actual Primary Completion Date :

Mar 1, 2013

Actual Study Completion Date :

May 1, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: single armed This is not a randomised trial, there is only one study group. All patients will receive cisplatin/gemcitabine chemotherapy in addition to oral daily dosing of selumetinib	Drug: selumetinib The starting dose of selumetinib will depend on the cohort. The first dose of selumetinib to be studied will be 75 mg twice daily (bd). Selumetinib will be taken every day (continuously) either once or twice a day, depending on the dose. Treatment with selumetinib may continue until disease progression. Other Names: AZD6244 Drug: gemcitabine gemcitabine: taken in combination with cisplatin will be given at 1000 mg/m2 in 250 - 500 ml 0.9% saline over 30 minutes by intravenous infusion on days 1, and 8 of each 21-day cycle for eight cycles in total Drug: cisplatin* cisplatin: 25 mg/m*2 in 1000 ml 0.9% saline given over 1 hour followed by 500mls 0.9% saline over 30 minutes followed by gemcitabine on days 1, and 8 of each 21-day cycle for eight cycles in total

Arm

Intervention/Treatment

Experimental: single armed

This is not a randomised trial, there is only one study group. All patients will receive cisplatin/gemcitabine chemotherapy in addition to oral daily dosing of selumetinib

Drug: selumetinib

The starting dose of selumetinib will depend on the cohort. The first dose of selumetinib to be studied will be 75 mg twice daily (bd). Selumetinib will be taken every day (continuously) either once or twice a day, depending on the dose. Treatment with selumetinib may continue until disease progression.

Other Names:

AZD6244

Drug: gemcitabine

gemcitabine: taken in combination with cisplatin will be given at 1000 mg/m*2 in 250 - 500 ml 0.9% saline over 30 minutes by intravenous infusion on days 1, and 8 of each 21-day cycle for eight cycles in total

Drug: cisplatin

cisplatin: 25 mg/m*2 in 1000 ml 0.9% saline given over 1 hour followed by 500mls 0.9% saline over 30 minutes followed by gemcitabine on days 1, and 8 of each 21-day cycle for eight cycles in total

Outcome Measures

Primary Outcome Measures

To investigate the safety and tolerability of the combination of cisplatin, gemcitabine and selumetinib, and to establish the recommended phase II dose of selumetinib when given in this combination. [from baseline to 28 days post last patient last treatment]
To investigate the safety and tolerability of the combination of cisplatin, gemcitabine (CisGem) and selumetinib and to establish the recommended phase II dose of selumetinib when given in this combination. The recommended dose of selumetinib to use in combination with CisGem in future studies will be the dose at which less than 33% of patients experience a DLT. The recommended dose will not be higher than 75mg/m*2

Secondary Outcome Measures

Response rate [From baseline to end of treatment]
To make a preliminary assessment of efficacy in terms of tumour control.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

A histopathological or cytological diagnosis of non-resectable, recurrent or metastatic biliary tract (intra- or extra-hepatic), gallbladder or ampullary carcinoma
ECOG performance status 0, 1, or 2
Age ≥ 18
Estimated life expectancy > 3 months
Adequate haematological function:
Haemoglobin 9g/dL (prior transfusions for patients with low haemoglobin are allowed)
WBC >/= 3.0 x 10*9/L
Absolute neutrophil count (ANC) >/= 1.5 x 10*9/L
Platelet count >/= 100 x 10*9/L
Adequate liver function:
Total bilirubin ≤1.5 x upper limit of normal (ULN) OR ≤ 3.0 x upper limit of normal (ULN) if stable for a duration of two weeks
ALT and/or AST & alkaline phosphatase ≤ 5 x ULN
Adequate renal function:
Serum urea and serum creatinine < 1.5 times ULN
Calculated GFR >/= 45 mL/min. If the calculated GFR is below 45ml/min, isotope EDTA confirmation of adequate renal function is required
Capable of giving written informed consent
Prior therapy is allowed (provided there has been a full recovery):
Surgery (non-curative operation), must have evidence on nonresectable disaes progression prior to trial entry
Radiotherapy, must have clear evidence of disease progression prior to inclusion
Prior adjuvant chemotherapy is allowed provided neither gemcitabine nor cisplation were used and treatment was completed 28 days prior to trial entry.

Exclusion Criteria:

Any prior exposure to MEK, Ras, or Raf inhibitors
Cardiac conditions as follows:
Uncontrolled hypertension (BP ≥150/95 despite optimal therapy)
Heart failure (NYHA Class II or above)
Prior or current cardiomyopathy
Baseline LVEF ≤50%
Atrial fibrillation with heart rate >100 bpm
Unstable ischaemic heart disease (MI within 6 months prior to starting treatment, or angina requiring use of nitrates more than once weekly).
Incomplete recovery from previous surgery.
Patients undergoing current treatment with curative intent.
History of prior malignancy that could interfere with the response evaluation (exceptions include in-situ carcinoma of the cervix treated by cone-biopsy/resection, non-metastatic basal and/or squamous cell carcinomas of the skin, any early stage (stage I) malignancy adequately resected for cure greater than 5 years previously).
Any evidence of severe or uncontrolled systemic diseases or laboratory finding that in the view of the investigator makes it undesirable for the patient to participate in the trial.
Any psychiatric or other disorder (e.g brain metastases) likely to impact on informed consent.
Pregnancy or breast-feeding. Women of child-bearing potential should must have a negative pregnancy test prior to study entry AND be using an adequate contraception method, which must be continued for 3 months after completion of chemotherapy
NB. Whilst not excluded, patients with significant impaired hearing must be made aware of potential ototoxicity and may choose not to be included. If included, baseline audiograms are recommended and should be followed by repeat audiograms prior to cycle