Pazopanib (Continuous vs Drug-free Interval Strategy) STAR Trial

Transcription

1 Pazopanib (Continuous vs Drug-free Interval Strategy) STAR Trial A Randomised Multi-Stage Phase II/III Trial of Standard first-line therapy (sunitinib or pazopanib) Comparing Temporary Cessation with Allowing Continuation, in the treatment of locally advanced and/or metastatic Renal Cancer ***See protocol for further details*** Available for Routine Use in Burton in-patient Derby in-patient Burton day-case Derby day-case Burton outreach chemotherapy clinic Derby outreach chemotherapy clinic Burton out-patient Derby out-patient Indication Locally advanced or metastatic clear cell renal cell carcinoma Treatment Intent Palliative Anti-Emetics Pre-chemotherapy Nil Post-chemotherapy A Day 1 Pazopanib 800mg Oral ONCE daily Frequency & duration: notes below) Every 42 days (6 weeks) continuously for 4 cycles (see Notes: 1. Inclusion criteria Full blood count: Haemoglobin (Hb) 9 g/dl Absolute Neutrophil Count (ANC) 1 x 10 9 /L Platelets 80 x 10 9 /L Renal biochemistry: Glomerular Filtration Rate (GFR) 30 ml/min (Cockcroft and Gault or Wright formula) Hepatobiliary function: Aspartate transaminase (AST) or alanine transaminase (ALT) 2.5 x Upper Limit of Normal (ULN) Bilirubin 1.5 x ULN, or in patients with Gilbert s syndrome 3 x ULN and direct bilirubin 35% AUTHORISED BY: Dr P Chakraborti PAGE 1 of 6

2 2. All patients will receive pazopanib for 4 cycles except in cases of unacceptable toxicity, disease progression or patients choice to stop treatment. After completion of 4 cycles of pazopanib patients will take up their allocated treatment arm: Conventional Continuation Strategy or Drugfree Interval Strategy, see below for details. 3. Conventional Continuation Stategy After completion of 4 cycles of pazopanib, patients will continue pazopanib. There is no change to scheduling or dose of pazopanib, excepting dose reductions for toxicity. 4. Drug-free Interval Strategy After completion of 4 cycles of pazopanib, patients will temporarily stop pazopanib (planned treatment break). They will remain off treatment until evidence of disease progression. At this time pazopanib will be restarted, and assuming further stable disease/response, continued for 4 cycles and following the same scheduling and dose as before. (When restarting pazopanib after a planned treatment break, disease progression must be confirmed Radiologically.) On restarting pazopanib, assuming further disease control is achieved, pazopanib is then planned to be continued for a minimum of 4 cycles. At this point, assuming ongoing disease control, consideration should be given to a further planned treatment break from pazopanib until evidence of progressive disease when pazopanib is again restarted. 5. A pazopanib cycle will not be extended due to dose interruptions in the cycle. If the treatment is stopped due to toxicity (or other medical reason) then these doses are omitted and not replaced. However, the start of a cycle may be delayed due to toxicities; delays of up to 28 days are acceptable. 6. Pazopanib should be taken without food, at least one hour before and two hours after a meal and tablets should be taken whole with water and not broken or crushed. If a dose is missed, the patient should be instructed not to replace the dose, but to take the next dose of pazopanib as planned. 7. Toxicity Dose delays Treatment may be delayed for up to 28 days to allow for resolution of toxicity (or other medical reason). Thus, if a cycle is completed or stopped, the next cycle must begin within 28 days from the date of completion or stopping. Any proposed delays greater than 28 days must be discussed with the Clinical Trials Research Unit. AUTHORISED BY: Dr P Chakraborti PAGE 2 of 6

3 Suggested dose modification tables below are for guidance only. They may be used at discretion of local investigator, but the current SPC (available via must always take precedence. Haematological toxicity: Neutropenia Grade 1 or 2 or grade 3 lasting < 5 days Grade 3 lasting 5 days Grade 4 Thrombocytopenia Grade 1 or 2 or grade 3 lasting < 5 days Grade 3 lasting 5 days Or Grade 4 Continue pazopanib at same dose. Monitor Withhold pazopanib until toxicity is Grade 2. Restart treatment at same dose. Withhold pazopanib until toxicity is Grade 2. Restart treatment at lower dose Continue pazopanib at same dose. Monitor. Withhold pazopanib until toxicity is Grade 2. Restart treatment at lower dose. Liver Toxicity: Cases of hepatic failure in a small minority of patients have been reported during use of pazopanib, which therefore requires careful liver. Administration of pazopanib to patients with mild or moderate hepatic impairment should be undertaken with caution and close monitoring, following local guidelines and information in the Summary of Product Characteristics (SPC). Patients who have restarted pazopanib after a treatment break will already have had several months of pazopanib treatment. However, there is little information on the risks of liver toxicity in such patients following recommencement of pazopanib. Liver function should therefore continue to be assessed before commencement of each cycle of pazopanib and investigators should exercise caution and are recommended to follow the guidelines for assessment of liver function at timings recommended as per the current pazopanib SPC. Hepatotoxicity Bilirubin < 1.5 x ULN (with any ALT/AST) Bilirubin >1.5 to 3 x ULN (with any ALT/AST) Continue pazopanib at current dose. Monitor LFTs in accordance with the current SPC Dose reduce to 200mg participants must therefore come off STAR trial AUTHORISED BY: Dr P Chakraborti PAGE 3 of 6

4 Bilirubin >3 x ULN (with any ALT/AST) ALT/AST 3.0 x ULN to 8.0 x ULN and total bilirubin 2.0 x ULN) AST/ALT>8.0 x ULN and any bilirubin AST/ALT elevations >3 x ULN concurrently with bilirubin elevations >2 x ULN Permanently stop pazopanib. Continue on pazopanib with weekly monitoring of liver function until transaminases return to Grade 1 or baseline. Interrupt pazopanib until transaminases return to Grade 1 or baseline. If the potential benefit for reinitiating pazopanib treatment is considered to outweigh the risk for hepatotoxicity, then reintroduce pazopanib at a reduced dose of 400 mg daily and measure serum liver tests weekly for 8 weeks. Following reintroduction of pazopanib, if transaminase elevations > 3 x ULN recur, then pazopanib should be permanently discontinued. Permanently discontinue pazopanib. Participants should be monitored until return to Grade 1 or baseline. Pazopanib is a UGT1A1 inhibitor. Mild, indirect (unconjugated) hyperbilirubinaemia may occur in participants with Gilbert's syndrome. Participants with only a mild indirect hyperbilirubinaemia, known or suspected Gilbert's syndrome, and elevation in ALT > 3 x ULN should be managed as per the recommendations outlined for isolated ALT elevations For other non-haematological toxicities see Protocol, section for details. Dose reductions Dose modifications for toxicities should be made according to local practice, (however, see recommended guidance in Protocol, section ) with reductions occurring in 200mg stages for pazopanib, see table below. AUTHORISED BY: Dr P Chakraborti PAGE 4 of 6

5 Dose Level Daily Pazopanib Dose (mg) A maximum of two dose reductions are allowed on the trial. Patients requiring dose reduction to less than 400mg/day pazopanib (i.e. more than two dose reductions) should permanently stop trial treatment. Dose re-escalation For participants who have received dose reduction on pazopanib, if the toxicity does not recur or worsen, the dose can then be increased stepwise back to 600mg and 800mg at the start of the next treatment cycle. 8. Concomitant medications (see SPC for more details) Treatment with strong inhibitors of CYP3A4 family (e.g itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole) may increase pazopanib concentrations. Grapefruit juice contains an inhibitor of CYP3A4 and may also increase plasma concentrations of pazopanib. Thus, these agents and grapefruit juice should be avoided during treatment with pazopanib, and selection of alternative concomitant medicinal products should be considered. Concomitant treatment with inducers of CYP3A4 such as rifampicin should be avoided due to risk of decreased exposure to pazopanib. Selection of an alternate concomitant medication with no or minimal enzyme induction potential is recommended. Concomitant use of pazopanib and simvastatin Concomitant use of pazopanib and simvastatin increases the incidence of ALT elevations. If a patient receiving concomitant simvastatin develops ALT elevations, discontinue simvastatin. In addition, concomitant use of pazopanib and other statins should be undertaken with caution. Medicines that raise gastric ph Co-administration of pazopanib with medicines that increase gastric ph should be avoided. If the concomitant use of a proton-pump inhibitor (PPI) is medically necessary, it is recommended that the dose of pazopanib be taken without food once daily in the evening concomitantly with the PPI. If the concomitant administration of an H2-receptor antagonist is medically necessary, pazopanib should be taken without food at least 2 hours before or at least 10 hours after a dose of an H2-receptor antagonist. Pazopanib should be administered at least 1 hour before or 2 hours after administration of short-acting antacids. AUTHORISED BY: Dr P Chakraborti PAGE 5 of 6

6 References: 1. STAR Protocol version 10, 22 nd May Summary of Product Characteristics (SPC) Pazopanib, 13-Dec-2016 (GlaxoSmithKline) <accessed >. AUTHORISED BY: Dr P Chakraborti PAGE 6 of 6