Hormone Therapy + Metformin (STAMPEDE Trial Arm K)

Transcription

1 Hormone Therapy + Metformin (STAMPEDE Trial Arm K) Systemic Therapy in Advancing or Metastatic Prostate Cancer: Evaluation of Drug Efficacy - A multi-arm randomised controlled trial *** See Protocol For Further Details *** Available for Routine Use in Burton in-patient Derby in-patient Burton day-case Derby day-case Burton community Derby community Burton out-patient Derby out-patient Indication Advancing or Metastatic prostate cancer Treatment Intent Palliative Anti-Emetics Pre-chemotherapy Nil Post-chemotherapy Nil Day 1 Metformin 850mg Oral once daily After 4-6 weeks, if tolerated increase to target dose of: Metformin 850mg Oral twice daily (Use trial stock) Frequency & duration: In the case of M0 patients, if androgen deprivation therapy (ADT) is stopped after a minimum of 2 years, metformin should continue for a minimum of 3 years following randomisation and for a further 12 months after the administration of the last luteinising hormone releasing hormone (LHRH) (whichever is longer). If ADT is not stopped, then metformin should continue as it the case for M1 patients. In the event that ADT is stopped and then re-started whilst patients remain on metformin (i.e. within 12 months of the last administration of LHRH) then metformin should continue whilst on ADT. If metformin is stopped 12 months after the last administration of LHRH it should not be re-started in the event of relapse. For M1 patients metformin should continue whilst on ADT. Treatment should continue post-progression providing it is judged to be in the patients best interest. AUTHORISED BY: Dr P Chakraborti PAGE 1 of 6

2 Notes: 1. Patients with known diabetes mellitus are not eligible for randomisation to the metformin arm of the trial. 2. All non-diabetic patients require an HbA1c to be performed and an assessment of renal function to determine glomerular filtration rate (GFR) prior to randomisation (see section for more details). 3. The standard of care for this patient group is androgen deprivation therapy (hormone therapy - see below) with or without docetaxel and for some patient groups, this should be supplemented with radiotherapy (see Section 6 of Protocol). 4. The recommended methods of hormone therapy (HT) are bilateral orchidectomy, LHRH analogues and LHRH antagonists. Patients having a bilateral orchidectomy are required to adhere to the same timelines as specified in Section 4.5.4, unless there is a strong clinical reason not to do so. Other methods of HT should be discussed with the Chief Investigator or the Trial Physician. The planned duration of HT should be at least 2 years. 5. Note that from trial protocol version 8.0 onwards, bicalutamide monotherapy is no longer a permitted trial therapy for new patients (but patients may switch to a permitted therapy to join the trial see Section of Protocol for further details). 6. Docetaxel is given according to local protocols as a standard non-trial treatment. The regime used previously within STAMPEDE was 75mg/m 2 Day 1 as 1hr IV infusion, plus prednisolone 5mg twice daily for 21 days repeated every 3 weeks for a maximum of 6 cycles. (See standard of care Docetaxel non-trial QACS for more information). 7. Patients should start metformin as soon as possible after randomisation, ideally 4 weeks from randomisation, 12 weeks from starting ADT. (Use specific STAMPEDE Metformin Arm K paper prescriptions provided). 8. Metformin and docetaxel can be given concurrently there is no need to wait until chemotherapy is complete. 9. Metformin hydrochloride should be taken from hospital stock (generic Metformin Hydrochloride may be used brands to be agreed with the Trial Office before dispensing to patients use trial specific stock). Both immediate and sustained release preparations can be used for the purpose of the trial. 10. Metformin should be taken around the same time each day and treatment tolerance is best if taken with or after food. For twice daily dosing, the minimum time between doses should be 8 hours, doses should not be taken closer together if forgotten or missed. Slow release preparations if taken once a day, should be taken with an AUTHORISED BY: Dr P Chakraborti PAGE 2 of 6

3 evening meal (Verbal advice from Trial team during teleconference training on new metformin arm, 16 th September 2016). 11. All patients will be seen in clinic two weeks after starting metformin treatment. Patients receiving concurrent docetaxel will be seen monthly until docetaxel treatment is completed. Post docetaxel patients will initially be seen in clinic 6 weekly once stable on treatment visits may become less frequent. Patients not on docetaxel treatment will be seen in clinic on a monthly basis initially, with visits again becoming less frequent once patients are stabilized on treatment. (Information from Dr Chakraborti, ). 12. Metformin Special Warnings Renal Impairment o Treatment should only be started in participants with stable renal function (GFR 45min/ml/1.73m 2 ). Renal function should be monitored at least every 6 months in participants with stable renal function, whilst on metformin. o If the GFR falls to between min/ml/1.73m 2 a dose reduction is required to ensure the maximum 24hr dose is 1000mg or less and monitoring of renal function is required at least 3 monthly. o Metformin should be permanently stopped if the GFR falls to 30mls/min/1.73m 2. o Renal function should be monitored at least every 6 months in participants with stable renal function and at least two to four times a year in participants with serum creatinine levels at the upper limit of normal and >75 years. o Additional monitoring is required in any patient at risk of deteriorating renal function (see Table 1 below). Lactic acidosis o Rare (3/100,000 patient years), but serious metabolic consequence of metformin intake. Reported cases have occurred primarily in diabetic patients with significant renal impairment who are also dehydrated. The risk factors for lactic acidosis are: renal impairment, prolonged fasting or malnutrition, excessive alcohol intake, hepatic insufficiency or any condition associated with hypoxia e.g. cardiac or respiratory failure or circulatory shock due to any cause. o Consider lactic acidosis in the event of non-specific symptoms such as muscle cramps, abdominal pain and/or severe weakness or lethargy. Any patient with a suspected metabolic acidosis requires immediate discontinuation of metformin and evaluation. Lactic acidosis is characterised by metabolic acidosis (decreased blood ph, high lactate above 5mmol/L and an increased anion gap and lactate/pyruvate ratio). The most effective way to remove lactate and metformin is haemodialysis. AUTHORISED BY: Dr P Chakraborti PAGE 3 of 6

4 Table 1: Situations when metformin treatment should be paused 13. Treatment breaks - It is anticipated that metformin treatment will be paused for approximately 72 hours around the time of contrast enhanced CT scans and may need to be paused during episodes of inter-current illness. Treatment pauses of 7 days or more should be recorded by updating the metformin treatment log. If metformin treatment is paused for more than 2 weeks, investigators may consider re-starting at 850mg once daily for the first 4 weeks before escalating to full dose providing tolerance is acceptable. It is suggested that, providing patients have a sufficient supply of labelled IMP metformin tablets, a telephone consultation may be sufficient to assess tolerance and advice regarding dose modification in order to limit hospital visits. If treatment is paused for more than 3 months or >50% of doses are missed for any reason the trial team should be informed as metformin may need to be discontinued. 14. Management of Specific Toxicities from Metformin Gastrointestinal disturbance - very common, include nausea, vomiting, diarrhoea, abdominal pain and loss of appetite - most common when first starting treatment. Grade 1 toxicity at 850mg immediate release (IR) twice daily: o Ensure metformin is taken with or after food o A. Change to 750mg sustained release (SR) twice daily OR o B. 1 week treatment pause then restart 850mg IR once daily & attempt an escalation to 850mg IR twice daily after 1 month OR AUTHORISED BY: Dr P Chakraborti PAGE 4 of 6

5 o C. Reduce to 500mg IR* once daily if both A&B unsuccessful & attempt dose escalation after 1 month TO 500mg IR twice daily, aiming to continue at the maximum tolerated dose Grade 2 or higher at 850mg immediate release (IR) twice daily: o A. Reduce to 500mg IR once daily; re-attempt dose escalation to 500mg IR twice daily after 1 week if symptoms improve. o B. Stop treatment for 2 weeks if A unsuccessful then re- start 750mg sustained release (SR) once daily after 2 weeks & re-attempt dose escalation to 750mg SR twice daily 2 months later, aiming to continue at the maximum tolerated dose Notes: For Grade 1 toxicity, Dr Chakraborti has agreed to try B first, followed by A and then C. Trial are happy for the prescriber to go straight to C if deemed necessary (Informed by Trial during teleconference training on new metformin arm, ). *Options are 500mg IR or SR Only 500mg IR will be used at this site. Confirmed with Dr Chakraborti Twice daily dose escalation confirmed with Trial during teleconference training on new metformin arm, Other possible metformin related toxicities are taste disturbance, skin reactions and B12 deficiency resulting in megalobastic anaemia and skin reactions (see Appendix C Table 6 of Protocol). Any patient who experiences anaemia whilst taking metformin should have haematinics including vitamin B12 measured and replaced if deficient. Metformin overdose Hypoglycaemia has not been reported with metformin doses up to 85g although lactic acidosis has rarely occurred in such circumstances. Patients should be urgently assessed in the event of an overdose and hospital admission considered. The management of metformin overdoses should be as per standard clinical care by the local team. The most effective way to remove lactate and metformin is haemodialysis. 15. Drug Interactions Metformin does not interact with any of the other treatments for prostate cancer and can be continued during all further treatments started on progression. Caution is needed however when initiating potential nephrotoxic drugs as metformin is renal excreted therefore may accumulate if renal function deteriorates. AUTHORISED BY: Dr P Chakraborti PAGE 5 of 6

6 Table 3: Drugs which require additional monitoring of renal function References: 1. STAMPEDE Trial Protocol Version 17, 19 th October STAMPEDE appendices Version, 16, 16 th October 2017, appendix C 3. STAMPEDE Pharmacy instructions, Version 14, 5 Th August STAMPEDE Metformin comparison Pharmacy v1.2, training presentation AUTHORISED BY: Dr P Chakraborti PAGE 6 of 6