Antineoplastic Agents

All Drugs and Chemicals

Olaparib

Poly(ADP-ribose) Polymerase Inhibitors

Enzyme Inhibitors

300mg olaparib + intrapatient dose escalation of AZD5363 4 days on, 3 days off

Schema for dose escalation in schedule A (4-days-on, 3-days-off AZD5363)

-1. Olaparib: 200mg, AZD5363 240mg

1. Olaparib: 300mg, AZD5363 320mg
2. Olaparib: 300mg, AZD5363 400mg
3. Olaparib: 300mg, AZD5363 480mg

300mg olaparib + intrapatient dose escalation of AZD5363 2 days on, 5 days off

Schema for dose escalation in schedule B (2-days-on, 5-days-off AZD5363)

-1. Olaparib: 200mg, AZD5363 400mg

1. Olaparib: 300mg, AZD5363 480mg
2. Olaparib: 300mg, AZD5363 560mg
3. Olaparib: 300mg, AZD5363 640mg

olaparib

AZD5363

Timothy A Yap, MBBS MRCP PhD

This is a phase I trial of the combination of the PARP inhibitor olaparib and AKT inhibitor AZD5363.

There are two parts to this study. Part A: dose escalation, and Part B: dose expansion.

Part A will investigate the combination of 300 mg bd of olaparib with intrapatient ascending doses of AZD5363 administered for either 4-days-on, 3-days-off, and 2-days-on, 5-days-off.

Once the Maximum Tolerated Dose (MTD) is reached for both arms (or under the advice from the Safety Review Committee (SRC) one of the schedules will be discontinued), the schedule with the optimum safety and PK/PD profile will be taken forward to a dose expansion phase (Part B).

Part B will evaluate the optimized dose/schedule identified in Part A of the study in patients with (1) BRCA1/2 mutant cancers (with previous disease progression on PARP inhibitor monotherapy), or (2) advanced sporadic tumours (e.g. TNBC, CRPC, HGSOC and tumours with somatic mutations or other aberrations known to result in a hyperactivated PI3K-AKT pathway).

Part A: The starting doses for both intermittent schedules will be 300 mg bd of olaparib and either AZD5363 given at 320 mg bd 4-days-on, 3-days-off, or 480 mg bd 2-days-on, 5-days-off. These starting doses are based on available data from the first-in-human studies \[D0810C00002\] (AstraZeneca) and \[D3610C00001\] (AstraZeneca) of both drugs, respectively.

A general schema for 3 potential dose levels to be pursued on the 4-days-on, 3-days-off AZD5363 schedule (Schedule A) and 2-days-on, 5-days-off AZD5363 schedule (Schedule B) in Part A of the study are listed below. The starting dose of olaparib will be fixed at 300mg bd in both schedules. These schema only provide general guidance; it will be possible for doses of one or both drugs to be escalated or de-escalated in a "seesaw" fashion contingent on the toxicity and/or PK/PD data reported. This may create dose cohort combinations not listed below. Both PK and PD data will be taken into consideration if available. With the exception of dose level 1, actual dose escalation/de-escalation will be determined following a discussion with the SRC during dose escalation teleconferences. Dose escalation will continue until MTD(s) are reached. Patients will be dosed on a flat scale and not by body weight or body surface area. Both schedules will be carried out in parallel.

Table 1: Schema for dose escalation in schedule A (4-days-on, 3-days-off AZD5363) Dose level (DL) olaparib bd AZD5363 bd 4d-on, 3d-off

* 1 200mg\* 240mg

  1. 300mg 320mg
  2. 300mg 400mg
  3. 300mg 480mg

     \*An intermediate dose of 250mg bd of olaparib may be considered depending on drug-related toxicities observed and patient tolerability

     Table 2: Schema for dose escalation in schedule B (2-days-on, 5-days-off AZD5363) Dose level (DL) olaparib bd AZD5363 bd 2d-on, 5d-off
* 1 200mg\* 400mg

  1. 300mg 480mg
  2. 300mg 560mg
  3. 300mg 640mg

     * An intermediate dose of 250mg bd of olaparib may be considered depending on drug-related toxicities observed and patient tolerability

After careful review of the clinical toxicity data, if the DLT is deemed to be caused by one of the agents, the responsible drug may be dose decreased and if well tolerated, the other agent maybe be increased in subsequent cohorts. If necessary, both drugs can also be dose de-escalated.

In Part A of the study, olaparib will be administered continuously with intermittent AZD5363 in 21-day cycles. Intrapatient dose escalation of AZD5363 will be utilised to evaluate different dose levels. The optimal dose schedule selected based on toxicity, PK-PD and/or efficacy data will be taken forward into two expansion cohorts in Part B of the study. Cohort 1 will comprise patients with germline BRCA1/2 mutated tumours, while Cohort 2 will comprise advanced sporadic cancers that may harbour HR defects (e.g. TNBC, CRPC and HGSOC) or those with somatic mutations or other aberrations known to result in a hyperactivated phosphatidylinositol-3-kinase (PI3K)-AKT pathway.

Trial of Olaparib in Combination With AZD5363 (ComPAKT)

A Phase I Multi-centre Trial of the Combination of Olaparib (PARP Inhibitor) and AZD5363 (AKT Inhibitor) in Patients With Advanced Solid Tumours

Changes in exploratory biomarkers, including pERK, RAD51, BRCA and PARP expression in pre- and post-treatment tumour biopsies

Correlate anti-tumour activity of the combination of olaparib and AZD5363 with the detection of putative predictive biomarkers of response and resistance in archival tumours and fresh tumour biopsies

Preliminary assessment of the antitumour putative predictive biomarkers of response and resistance to the combination of olaparib and AZD5363.

Evaluate a novel experimental trial design involving intrapatient dose escalation of AZD5363 in combination with olaparib.

Dose at which no more than one out of six patient at the same dose level experiences a probable drug-related dose limiting toxicity.

Plasma levels of olaparib and AZD5363 using validated assays.

Changes in platelet rich plasma, hair follicles and pre- and post-treatment tumour biopsies using validated assays

Institute of Cancer Research, United Kingdom

AstraZeneca

Royal Marsden NHS Foundation Trust

Neoplasms

All Conditions

Respiratory Tract (Lung and Bronchial) Diseases

Carcinoma

Carcinoma, Non-Small-Cell Lung

Lung Neoplasms

Respiratory Tract Neoplasms

Thoracic Neoplasms

Lung Diseases

Respiratory Tract Diseases

Carcinoma, Bronchogenic

Bronchial Neoplasms

Sorafenib

Protein Kinase Inhibitors

sorafenib (400mg or 600mg or 800mg) by mouth twice daily, for 28 days

sorafenib

Anne M Traynor, M.D.

The purpose of this study is to determine the number of patients with advanced, relapsed non-small cell lung cancer who can tolerate dose escalation sorafenib from 400 mg twice daily to either 600 mg twice daily or 800 mg twice daily. Safety and tolerability of sorafenib will also be examined.

Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related mortality in the U.S. Time to progression in advanced disease remains poor and further study of newer agents with novel mechanisms of action is needed to improve duration and quality of life for NSCLC patients.

Sorafenib is an oral-multi-kinase inhibitor with effects on tumor proliferation and tumor angiogenesis. Sorafenib has demonstrated activity in preclinical models of NSCLC both in combination with chemotherapy and as monotherapy. A recent intra-patient dose escalation trial of sorafenib in renal cell carcinoma showed positive response rates and tolerability up to 1200mg in 91% of patients.

This study attempts a similar dose-escalation of sorafenib in NSCLC patients.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Trial of Olaparib in Combination With AZD5363 (ComPAKT)	NCT02338622	Advanced Cancer	olaparib AZD5363	18 Years -	Royal Marsden NHS Foundation Trust
Intra-patient Dose Escalation Study of Sorafenib in Advanced Non-small Cell Lung Cancer	NCT00954278	Carcinoma, Non ...	sorafenib	18 Years -	University of Wisconsin, Madison
Trial of Olaparib in Combination With AZD5363 (ComPAKT)	NCT02338622	Advanced Cancer	olaparib AZD5363	18 Years -	Royal Marsden NHS Foundation Trust

Spots Global Cancer Trial Database for intrapatient dose escalation