Clinical trial NCT00777582: Phase I Comparative Bioavailability Study
Official title: A Phase I, Randomised, 2 Period Cross Over Study to Determine the Comparative Bioavailability of Two Different Oral Formulations of AZD2281 in Cancer Patients With Advanced Solid Tumours
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE1
Conditions: Solid Tumors
Keywords: Poly (ADP ribose) polymerases
Homologous Recombination Deficiency (HRD)
Advanced solid tumours
Lead sponsor: AstraZeneca
Sponsor class: INDUSTRY
First posted: 2008-10-22
Enrollment: 197
Sex: ALL
Minimum age (years): 18
Maximum age (years): 130
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: BASIC_SCIENCE

Brief summary: The purpose of this phase I randomised cross over study is to determine and compare the bioavailability of two different oral formulations of AZD2281 in advanced solid tumour cancer patients


Eligibility criteria: Inclusion Criteria:

* Histologically confirmed malignant advanced solid tumour, which is refractory to standard therapies (except Group 8 patients who must not be platinum refractory) or for which no suitable effective standard therapy exists
* Patients must have adequate organ and bone marrow function measured within 7 days prior to administration of study treatment
* Female patients must have evidence of non-child bearing status: negative urine or serum pregnancy test within 7 days of study treatment for women of child bearing, or postmenopausal status

Exclusion Criteria:

* Patients receiving chemotherapy, radiotherapy (except for palliative reasons) or any other anti-cancer therapy within 4 weeks of the last dose prior to study entry. Patients may continue the use of biphosphonates for bone metastases and corticosteroids
* Patients with symptomatic uncontrolled brain metastases
* Major surgery within 2 weeks of starting study and patients must have recovered from any effects of any major surgery
* Patients who are platinum refractory (Group 8 only)
* Patients with myelodysplastic syndrome/acute myeloid leukaemia (Group 8 only).

Primary outcomes:
measure: PK Phase Primary Outcome: To determine the comparative bioavailability of a new tablet formulation of AZD2281 compared to the existing capsule formulation
timeFrame: Blood samples (12) will be taken at pre-defined intervals following dosing of a single capsule and a single tablet dose
measure: Continued Supply Phase: To enable patients to continue to receive treatment with AZD2281. Safety and tolerability data will be collected to further determine the safety and tolerability of the capsule formulation of AZD2281 in these patients
timeFrame: every 28 days
measure: Continued Supply Expansion Phase: To compare the safety and tolerability of the tablet and capsule formulation of AZD2281 in all patients: Safety, AEs, Physical Exam, vital signs
timeFrame: at every visit
measure: Dose Escalation Phase of continued supply expansion: To determine safety & tolerability of higher than 200mg bid (to 400mg) of tablet & compare safety & tolerability profile of tablet with 400mg capsule
timeFrame: at every visit
measure: Randomised tablet formulation continued supply expansion phase (Group 8): To determine the safety and tolerability profile of selected tablet dose schedules of the melt-extrusion (tablet) formulation.
timeFrame: at every visit
Secondary outcomes:
measure: PK Phase Secondary Outcome: To generate single dose PK data for the new tablet formulation in man, and to generate information on dose linearity for the new tablet formulation
timeFrame: Blood samples (12) will be taken at pre-defined intervals prior to and following dosing of a single capsule and a single tablet dose
measure: To compare the extent of PARP inhibition achieved in peripheral blood mononuclear cells (PBMCs) following dosing of both the new tablet formulation and existing capsule formulation
timeFrame: Blood samples (4) will be taken at pre-defined intervals prior to and following dosing of a single capsule and a single tablet dose
measure: To determine the safety and tolerability of AZD2281 for both the new tablet formulation and existing capsule formulations
timeFrame: every 28 days
measure: Continued Supply Expansion Phase: To compare the steady state exposure achieved with 200mg bid tablet formulation and 400mg bid capsule formulation
timeFrame: at visit 3 and visit 4
measure: Continued Supply Expansion Phase: To describe the efficacy data observed in patients treated with the capsule and the tablet
timeFrame: RECIST, Progression Free Survival, Best overall response and CA-125 response
measure: Dose Escalation Phase of the continued supply expansion: To determine the single dose and steady state exposures achieved with higher doses of AZD2281 tablet formulation
timeFrame: at every visit
measure: Dose Escalation Phase of the continued supply expansion: To compare between patients the single dose and steady state exposures of AZD2281 achieved with selected tablet doses and the 400mg bid capsule dose
timeFrame: at every visit
measure: Dose Escalation Phase of the continued supply expansion: To describe the efficacy data observed in patients treated with the capsule formulation and the tablet formulation
timeFrame: at every visit
measure: Randomised tablet formulation continued supply expansion phase (Group 8): To determine the single dose and steady state exposures achieved with the selected table dose schedules of AZD2281 melt-extrusion (tablet) formulation
timeFrame: at every visit
measure: Randomised tablet formulation continued supply expansion phase (Group 8): To obtain a preliminary assessment of the effect of food on the exposure to AZD2281 following dosing of the melt-extrusion (tablet) formulation.
timeFrame: at every visit
measure: Randomised tablet formulation continued supply expansion phase (Group 8): To describe the efficacy data observed in patients treated with the melt-extrusion (tablet) formulation
timeFrame: at every visit
Other outcomes:
Locations:
city: Randwick
country: Australia
facility: Research Site
city: Leuven
country: Belgium
facility: Research Site
city: Bellinzona
country: Switzerland
facility: Research Site
city: Edinburgh
country: United Kingdom
facility: Research Site
city: London
country: United Kingdom
facility: Research Site
city: Manchester
country: United Kingdom
facility: Research Site
city: Newcastle upon Tyne
country: United Kingdom
facility: Research Site
city: Northwood
country: United Kingdom
facility: Research Site
city: Oxford
country: United Kingdom
facility: Research Site
city: Sutton
country: United Kingdom
facility: Research Site
Study officials:
affiliation: AstraZeneca
name: Jane Robertson, BSc, MBCHB, MD
role: STUDY_DIRECTOR
affiliation: Royal Marsden NHS Foundation Trust
name: Stan Kaye, Professor
role: PRINCIPAL_INVESTIGATOR
References:
citation: Mateo J, Moreno V, Gupta A, Kaye SB, Dean E, Middleton MR, Friedlander M, Gourley C, Plummer R, Rustin G, Sessa C, Leunen K, Ledermann J, Swaisland H, Fielding A, Bannister W, Nicum S, Molife LR. An Adaptive Study to Determine the Optimal Dose of the Tablet Formulation of the PARP Inhibitor Olaparib. Target Oncol. 2016 Jun;11(3):401-15. doi: 10.1007/s11523-016-0435-8.
citation: Matulonis UA, Penson RT, Domchek SM, Kaufman B, Shapira-Frommer R, Audeh MW, Kaye S, Molife LR, Gelmon KA, Robertson JD, Mann H, Ho TW, Coleman RL. Olaparib monotherapy in patients with advanced relapsed ovarian cancer and a germline BRCA1/2 mutation: a multistudy analysis of response rates and safety. Ann Oncol. 2016 Jun;27(6):1013-1019. doi: 10.1093/annonc/mdw133. Epub 2016 Mar 8.
citation: Ang JE, Gourley C, Powell CB, High H, Shapira-Frommer R, Castonguay V, De Greve J, Atkinson T, Yap TA, Sandhu S, Banerjee S, Chen LM, Friedlander ML, Kaufman B, Oza AM, Matulonis U, Barber LJ, Kozarewa I, Fenwick K, Assiotis I, Campbell J, Chen L, de Bono JS, Gore ME, Lord CJ, Ashworth A, Kaye SB. Efficacy of chemotherapy in BRCA1/2 mutation carrier ovarian cancer in the setting of PARP inhibitor resistance: a multi-institutional study. Clin Cancer Res. 2013 Oct 1;19(19):5485-93. doi: 10.1158/1078-0432.CCR-13-1262. Epub 2013 Aug 6.
citation: Sandhu SK, Omlin A, Hylands L, Miranda S, Barber LJ, Riisnaes R, Reid AH, Attard G, Chen L, Kozarewa I, Gevensleben H, Campbell J, Fenwick K, Assiotis I, Olmos D, Yap TA, Fong P, Tunariu N, Koh D, Molife LR, Kaye S, Lord CJ, Ashworth A, de Bono J. Poly (ADP-ribose) polymerase (PARP) inhibitors for the treatment of advanced germline BRCA2 mutant prostate cancer. Ann Oncol. 2013 May;24(5):1416-8. doi: 10.1093/annonc/mdt074. Epub 2013 Mar 22. No abstract available.