GDC-0068 with docetaxel or mFOLFOX for advanced solid tumours

• Research type

  Research Study

• Full title

  A Phase 1b, Open-Label, Dose-Escalation Study of the Safety and Pharmacology of GDC-0068 in Combination with either Docetaxel or Fluoropyrimidine Plus Oxaliplatin in Patients with Advanced Solid Tumours

• IRAS ID

  79253

• Contact name

  Rhoda Molife

• Sponsor organisation

  Genentech, Inc

• Eudract number

  2011-000782-13

• ISRCTN Number

  ISRCTN

• Research summary

  Research Summary
  Akt is the central node of the PI3K-Akt-mTOR pathway ?? this pathway is the most commonly activated and mutated (abnormal) signalling pathway in cancers. The Akt protein plays a role in cancer growth and spread, survival and resistance to treatment. When mutated, the growth of cancer cannot be controlled and resistance to standard treatments develops. There is therefore strong justification for developing cancer treatments that target Akt.GDC-0068 is an inhibitor of Akt. In laboratory experiments, GDC-0068 was able to increase the anti-cancer effects of standard chemotherapies like docetaxel, 5-FU and cisplatin ?? a drug similar to oxalipatin. GDC-0068 is currently being tested in a Phase 1a study to assess its safety, tolerability and pharmacokinetics (PK; how the body absorbs, distributes, breaks down and removes the drug). As of 17 Nov 2010, 15 patients have been enrolled in this study and GDC-0068 has been well tolerated.The purpose of this Phase 1b dose escalation study is to assess the safety, tolerability and PK of GDC-0068 administered in combination with docetaxel (Arm A) or mFOLFOX6 chemotherapy (5-FU and leucovorin [folic acid] and oxaliplatin; Arm B) in patients with advanced cancer where standard treatment does not exist or has proven ineffective or intolerable. There are 2 stages within each arm: a dose escalation stage (Stage 1) and an expansion stage (Stage 2). Stage 1 is designed to determine the maximum tolerated dose (MTD) of GDC-0068 in combination with docetaxel or mFOLFOX6. Patients will be treated at increasing doses of GDC-0068 in groups of 3-6 patients until the MTD is reached. Additional patients will be enrolled in Stage 2 at the MTD to confirm a potential dose for further investigation.In Arm A, GDC-0068 will be given orally on days 2-14, and docetaxel on day 1 in each 21-day cycle. In Arm B, GDC-0068 will be given on days 1-7 in each 14-day cycle. 5-FU will be given on day 1 and continuously over the next 46 hours, every 14 days. Oxaliplatin will be given on day 1 every 14 days. Patients will attend for study visits 2-5 times per cycle. Study procedures will include physical examination, vital signs, ECGs, CT scans, bone scans MRI, blood and urine sampling. Patients can continue on study drug until disease progression or intolerable side effects.This study is sponsored by Genentech, Inc. Approximately 21 to 48 patients per arm will participate in this study in Europe and the United States with approximately 15-20 patients from the Royal Marsden Hospital.

  Summary of Results
  The primary objectives of the study were met at the interim analysis (data cut-off 02 May 2016), as reported in the interim CSR (Report No. 1074119. June 2017).
  The overall conclusions of the study at the final analysis (last patient last visit date 16 October 2020) are as follows: The overall safety of ipatasertib at the final analysis remained consistent with the interim CSR. Ipatasertib was generally well tolerated at doses of up to 600 mg with AEs that were generally reversible and manageable. The most common AEs observed in Arm D were diarrhoea, nausea, vomiting, neutropenia, decreased appetite, and fatigue. This safety profile was generally consistent with the established safety profile of the PI3K-Akt-mTOR inhibitor class and the known safety profile of the drugs used as combination partners.
  • An additional DLT was identified in the final analysis for Arm D. The Grade 3 AE of rash maculo-papular had onset on Study Day 11 but was flagged as a DLT only after the interim analysis and therefore appears as a new DLT in the final analysis. Prior to this, the only DLT reported in the study was an event of dehydration in a patient in Arm C. There were no changes since the interim analysis to conclusions for MAD, recommended phase II dosing, PK, or antitumor activity/efficacy, which are provided below for completeness:
  • The MAD for ipatasertib in combination with docetaxel (Arm A) was 600 mg given orally daily for Days 2–15 of each 21–day cycle. The MAD for ipatasertib in combination with mFOLFOX6 (Arm B) was 600 mg given orally daily for Days 1–7 of each 14–day cycle. The MAD for ipatasertib in combination with paclitaxel (Arm C) was 600 mg, and patients in the expansion cohort were treated with 400 mg ipatasertib. The MAD for ipatasertib in combination with enzalutamide in patients with metastatic CRPC (Arm D) was 600 mg given orally daily for Days 1–28 of each 28–day cycle.
  • Based on the safety results of Arm B, the recommended dose for the Phase II GO28341 study of ipatasertib in combination with mFOLFOX6 for the treatment of gastric cancer was 600 mg daily.
  • Based on the safety results of Arm C, the recommended dose for the Phase II GO29227 study of ipatasertib in combination with paclitaxel for the treatment of triple-negative breast cancer was 400 mg daily for Days 1–21 of each 28–day cycle.
  • The PK results showed:
  • Exposures of docetaxel, mFOLFOX6 (5-FU, free and total oxaliplatin), paclitaxel (and its metabolite, 6-alpha-hydroxy paclitaxel), and enzalutamide (and its metabolite, N desmethyl enzalutamide) were comparable to that reported in the literature.
  • Ipatasertib concentrations in combination with docetaxel, mFOLFOX6, and paclitaxel were generally comparable to those observed in the single–agent study, wherein ipatasertib was administered alone.
  • Ipatasertib exposures decreased by approximately 50% when co-administered with enzalutamide, a strong CYP3A inducer, indicating that CYP3A is a key enzyme responsible for ipatasertib metabolism.
  • Ipatasertib combination therapy showed evidence of anti-tumour activity in diverse tumour types, including partial remission in patients with breast, lung, colorectal, and oesophageal cancer and metastatic CRPC.
  Has the registry been updated to include summary results?: No
  If yes - please enter the URL to summary results:
  If no – why not?: No, sponsor has not updated ClinicalTrials.gov or https://eur03.safelinks.protection.outlook.com/?url=http%3A%2F%2Furl6570.hra.nhs.uk%2Fls%2Fclick%3Fupn%3DouFFm-2FZqrUn2jjUD5TieZBfigX0bV4wUGi1E343XhAvX3yVhzvwFNscFn-2FUC0vTFUKcX_E1aO2-2BZlVOSJJV-2FajQqskegTd6IRomHYTi-2Fbt8SH3YKWvskV8YDce6m9vGnZd08r-2B1ZRmNaQCP8rqa1KKdmgqYiU-2FmNB6WzDk3UWGP1Kj6qveBJSog8ZW8Pdewipl04Bv1BpCH2loqA0A53IPYbnyMdInA5txrERACyO37afSx2ob7rRHOFLo4lri0zmoNYCObQMWrzcqED1H8Osugiq2A-3D-3D&data=04%7C01%7Capprovals%40hra.nhs.uk%7C8e21aa4cb27e4c90eeac08d9e7089fa4%7C8e1f0acad87d4f20939e36243d574267%7C0%7C0%7C637794846483753578%7CUnknown%7CTWFpbGZsb3d8eyJWIjoiMC4wLjAwMDAiLCJQIjoiV2luMzIiLCJBTiI6Ik1haWwiLCJXVCI6Mn0%3D%7C3000&sdata=7KygPbgY%2FF%2FrW76CxwRTTh7FMGQDTSdl2%2FimAjFu%2Big%3D&reserved=0 with study results. However, study results can be found in the CSR synopsis provided to all participating centres.

• REC name

  London - Central Research Ethics Committee

• REC reference

  11/LO/0841

• Date of REC Opinion

  1 Aug 2011

• REC opinion

  Further Information Favourable Opinion