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Pink Sheet – Master Protocols In Practice

Pink Sheet – Master Protocols In Practice

Executive Summary

Basket trials are building a path for tissue-agnostic drug development in oncology, and plans are proceeding for more master protocols in pediatric cancers, acute myeloid leukemia and pancreatic cancer.


Master protocol trial designs are slowly gaining ground, especially in oncology development, as results have emerged from the early generation of basket and umbrella trials.


Basket trial data was crucial to the approval of FDA’s first tissue-agnostic oncology indication on May 23, 2017, when Merck & Co. Inc. ‘s Keytruda (pembrolizumab) received accelerated approval for patients defined by a biomarker (microsatellite instability-high or mismatch repair deficient cancers) rather than a tumor’s anatomical location of origin. (Also see “Biomarker-Led Claim Is Small Step For Merck’s Keytruda, Giant Leap For Cancer Indications” – Pink Sheet, 23 May, 2017.)


NDA filings are predicted by early 2018 for two more tissue-agnostic indications based on master protocols, for Loxo Oncology Inc. ‘s larotrectinib (the NAVIGATE basket trial) and Ignyta Inc.’s entrectinib (STARTRK2, also a basket trial). Both drugs are kinase inhibitors being studied for NTRK fusion-positive solid tumors. (Also see “Oncology: Tissue-Agnostic Indications Advance Under US FDA’s Breakthrough Umbrella” – Pink Sheet, 25 May, 2017.)

After I-SPY2

Merck’s Keytruda is also the latest graduate from the I-SPY2 master protocol, which looks for drugs that show promising pathological complete response (pCR) data as a surrogate marker for disease-free survival in neoadjuvant treatment of high-risk breast cancer. I-SPY2 started in 2010. (Also see “Biomarkers Consortium Launches Adaptive Trial To Test Targeted Breast Cancer Drugs” – Pink Sheet, 19 Mar, 2010.)


At the American Society for Clinical Oncology annual meeting in June, Merck announced that Keytruda had “graduated” I-SPY2 in three genetic signatures: triple-negative breast cancer; hormone receptor-positive/HER2-negative breast cancer; and all HER2-negative (including the other segments). The company expects it will need to conduct a controlled study with the pCR endpoint in a large number of patients if it wishes to pursue FDA approval. (Also see “Merck’s Keytruda Offers Hope And Risk In Early Breast Cancer” – Pink Sheet, 6 Jun, 2017.)


At least five other neoadjuvant breast cancer regimens have graduated I-SPY2, but only two have been further tested in that setting: Puma Biotechnology Inc.’s neratinib and AbbVie Inc.’s veliparib. (Also see “I-SPY Graduates: Where Are They Now?” – Pink Sheet, 10 Jul, 2016.) Unfortunately, results of subsequent trials have been mixed. (Also see “Puma’s Neratinib SUMMIT Study Shows Potential & Pitfalls Of Precision Medicine” – Pink Sheet, 2 Apr, 2017.) and (Also see “Veliparib Phase III Failures Strike Blow To AbbVie’s Oncology Strategy” – Pink Sheet, 20 Apr, 2017.)


Roche’s VE-BASKET master protocol trial of Zelboraf (vemurafenib) in nonmelanoma cancer patients with BRAF V600 mutations also produced mixed results, suggesting that tumor histology still had an important role. (Also see “Tissue-Agnostic Approach To Cancer Drug Development Takes A Hit” – Pink Sheet, 14 Sep, 2015.) The company is nonetheless moving ahead with basket trials, including the “My Pathway” study of four of its drugs in patients with actionable mutations who have no available beneficial therapy. (Also see “Milestones In Basket Trials: Roche’s VE-BASKET And ‘My Pathway'” – Pink Sheet, 14 Sep, 2015.)


Actors as various as the American Society for Clinical Oncology, the National Cancer Institute and Novartis AG are also pursuing basket trials to identify promising oncology candidates for genomically defined patient populations. (Also see “Genomics-Driven Trials Built To Be Fast And Flexible” – Pink Sheet, 21 Sep, 2015.)


The venerable Lung-MAP master protocol trial in rare squamous subsets of non-small cell lung cancer (NSCLC) continues with high hopes for reducing trial costs and improving efficiency. (Also see “Lung-MAP Patient Screening Should Translate To Cost-Savings” – Pink Sheet, 23 Jun, 2014.) and (Also see “Lung Cancer “Master Protocol” Eyed As Paradigm-Changing Approach To Drug Development” – Pink Sheet, 18 Nov, 2013.) The trial has had to change design elements to account for the new standard of care set by FDA’s approval of Bristol-Myers Squibb Co.’s Opdivo (nivolumab) in the space. (Also see “Master Protocols Are Both Welcome And Inevitable – US FDA’s Woodcock” – Pink Sheet, 6 Jul, 2017.)

The Next Wave Of Master Protocols

As researchers become more familiar with master protocol trials and adaptive statistics, more master protocols – basket, umbrella and platform trials – are in the works. Settings include:


  • Pediatric cancers (Also see “Genentech Wants Other Firms’ Compounds For Mass Pediatric Cancer Screening” – Pink Sheet, 7 Mar, 2017.) and (Also see “FDA Encourages Pediatric Master Protocols With Bayesian Approach” – Pink Sheet, 27 Sep, 2016.)
  • Acute myeloid leukemia (Also see “AML Master Protocol For Precision Medicine Developed By Nonprofit And US FDA” – Pink Sheet, 21 Dec, 2016.)
  • Pancreatic cancer (Also see “Biomarkers For Pancreatic Cancer To Be Tested In Multi-drug Collaborative Study” – Pink Sheet, 6 Oct, 2016.)
  • Metastatic breast cancer (Also see “Master Protocol For Metastatic Breast Cancer Needs To Adapt To Rational Combinations” – Pink Sheet, 17 Dec, 2014.)


The number of master protocol trials is only likely to keep rising with continued advances in next-generation sequencing (NGS) technology and pharmacogenomic analysis. (Also see “One Size No Longer Fits All: The Personalized Medicine Trial Landscape” – Pink Sheet, 20 Mar, 2017.) and (Also see “Q&A: FDA Dx Reviewer’s Tips For Next-Gen Sequencing Sponsors” – Pink Sheet, 22 Jun, 2017.)