This study is a Phase Ib, open label, multi-centre, dose escalation trial to assess the dose of lithium that can be safely combined with standard treatment oxaliplatin and capecitabine chemotherapy.
Registered patients will be treated with lithium combined with a standard chemotherapy regimen of oxaliplatin and capecitabine until a maximum of 6 x 21 day cycles (18 weeks), tumour progression, unacceptable toxicity, pregnancy, withdrawal of consent or withdrawal at the discretion of the investigator, whichever occurs first.
After discontinuation of study treatment, all patients will be followed for safety for at least 30 days.
Patients who discontinue treatment for reasons other than disease progression will continue to be followed every 9 weeks in accordance with standard of care for efficacy (i.e. tumour assessment) until disease progression, death, withdrawal of consent, loss to follow up or until the start of a new anti-neoplastic treatment, whichever occurs first.
Once the patient has documented disease progression, they will be followed up every three months (±1 month) for survival status.
The trial will be a traditional 3+3 design: cohorts of 3 patients will be treated with lithium combined with standard treatment oxaliplatin and capecitabine chemotherapy.
The doses of oxaliplatin and capecitabine have been established in prior phase II and III studies and will not be escalated. Lithium target serum concentrations are assigned at registration according to a defined dose escalation scheme. Study lithium dose escalation will follow a modified Fibonacci 3+3 sequence.
A -1 dose level (0.4mmol/L) is included in case dose de-escalation is needed.
The levels of lithium achieved in each patient will be established by regular assessment of steady state serum concentrations.
Lithium will start at a low level and dose escalations will be performed in cohorts of 3 patients according to a standard 3+3 algorithm.
Dose escalation and determination of MTD will be based on the occurrence of Dose Limiting Toxicities (DLT) as defined below.
The first cohort of 3 patients will commence at dose level 1. All patients in each cohort will be observed for two cycles on the specified dose:
* If none of 3 patients at a given dose level experiences a DLT, accrual will continue to the next dose level according to the protocol.
* If 1 of 3 patients experiences a DLT at a given dose level, 3 additional patients will be treated at the same dose. If no additional patient has a DLT in this cohort, accrual will continue to the next dose level according to the protocol.
* If 2 or more patients in 3 or 6 patients treated at a given dose experience a DLT, the next lowest dose level will define the MTD.
A Dose Limiting Toxicity (DLT) is defined as any of the following adverse events occurring during the two first cycles (within 42 days from first dose) of treatment and possibly, probably or definitely related to the combination of lithium, oxaliplatin and capecitabine:
A. Grade 3 or 4 non-haematological toxicity other than nausea, vomiting or fatigue.
B. Grade 3 or 4 thrombocytopenia: grade 4 thrombocytopenia (platelet count \< 25 x 109/L) or grade 3/4 thrombocytopenia (grade 3 platelet count: 25 x 109/L to \< 50 x 109/L) associated with bleeding.
C. Complicated grade 4 neutropenia (\< 0.5 x 109/L): fever, sepsis \> 5 days of duration.
D. Any significant\* grade 2 and higher toxicity other than nausea, vomiting, rash, alopecia or anaemia that persists longer than 35 days after the start of cycle 1.
\*"Significant" defined as affecting quality of life or patient safety as determined by investigator.
Clinical and laboratory parameters will be assessed to evaluate disease response and toxicity of study therapy. Safety assessments will be performed every 3 weeks for the 18 weeks. Efficacy assessments (Radiological examination) will be performed on all patients every 9 weeks (+/- 1 week).
An End of Treatment visit will be performed for patients within 30 days (+/- 1 week) post last dose or disease progression.
