1049PD - A phase 1b study (SCORES) assessing safety, tolerability, pharmacokinetics, and preliminary anti-tumor activity of durvalumab combined with AZD9150...

Date 10 October 2016
Event ESMO 2016 Congress
Session Immunotherapy of cancer
Topics Cancer Immunology and Immunotherapy
Head and Neck Cancers
Presenter David Hong
Citation Annals of Oncology (2016) 27 (6): 359-378. 10.1093/annonc/mdw378
Authors D. Hong1, G. Falchook2, C.E. Cook3, W. Harb4, P. Lyne5, P. McCoon6, M. Mehta3, P. Mitchell7, G.M. Mugundu8, M. Scott3, J.S. Wang9
  • 1Investigational Cancer Therapeutics, MD Anderson Cancer Center, 77030 - Houston/US
  • 2Drug Development, Sarah Cannon Research Institute at HealthONE, 80218 - Denver/US
  • 3Early Clinical Development, AstraZeneca Pharmaceuticals, Waltham/US
  • 4Horizon Oncology Center, Unity Campus, Lafayette/US
  • 5Oncology Imed, AstraZeneca Pharmaceuticals, Waltham/US
  • 6Translational Science, AstraZeneca Pharmaceuticals, Waltham/US
  • 7Early Clinical Biometrics, AstraZeneca Pharmaceuticals, Waltham/US
  • 8Qunatitative Clinical Pharmacology, Early Clinical Development, AstraZeneca Pharmaceuticals, Waltham/US
  • 9Drug Development Unit, Florida Cancer Specialists/Sarah Cannon Research Institute, Sarasota/US

Abstract

Background

Activating the immune system for therapeutic benefit in cancer has long been a goal in immunooncology. Combining a PD-L1 antagonist, durvalumab (D), with novel agents targeting immunosuppression in the tumor bed such as AZD9150 (A9, an antisense oligonucleotide against STAT3) or AZD5069 (A5, a CXCR2 antagonist) may strongly enhance anti-tumor responses.

Methods

Patients (pts) with advanced solid malignancies (N = 31) were enrolled using a CRM–based approach to identify dose combinations of A9 + D and A5 + D with an incidence of dose-limiting toxicities (DLT) less than 33%. Up to 6 evaluable pts per cohort were initially assessed. For all, D was fixed at 20 mg/kg Q4W with A9 at dose levels (DL) of (1) 2mg/kg QW or (2) 3mg/kg QW i.v; A5 was started at DL1 40 mg po bid, then DL2 80 mg bid. The primary objective was to determine the MTD and recommended phase II dose (RP2D), and secondarily safety, PK, pharmacodynamics, biological and clinical activity for each combination.

Results

In the A9 + D arm, 11 pts (DL1 = 4, DL2 = 7) were treated. The most common drug related adverse events (AEs) were thrombocytopenia (64%), neutropenia (45%) and ALT/AST increase (36%) with no DLTs or drug-related Gr 4 events. The MTD/RP2D for AZD9150 was 3 mg/kg QW. In the A5 + D arm, 20 pts were enrolled (DL1 = 9; DL2 = 11) with most common drug related AEs of neutropenia (35%), fatigue or anorexia (20%). One DLT of Gr 3 neutropenia occurred at 40 mg bid; 2 similar DLTs were noted at DL2. The MTD/RP2D for AZD5069 was 40 mg po bid. Two pts in the A9 + D arm achieved a confirmed PR (MSH2/6 mutant mCRPC, GE jxn tumor) per modified iRECIST. Three more pts on A9 + D (laryngeal, colorectal, leiomyosarcoma) and two on A5 + D (breast, urothelium) demonstrated stable disease; the last pt's course was clearly consistent with pseudoprogression. Target engagement was shown in peripheral blood of A9 + D (STAT3 knockdown) and A5 + D (CXCR2-elicited cytokines) pts.

Conclusions

Combinations of durvalumab with AZD9150 or AZD5069 have a manageable toxicity profile and encouraging evidence of activity. Enrollment into phase 2 SCCHN expansion cohorts continues. Pharmacokinetic and pharmacodynamic data will be presented.

Clinical trial identification

NCT02499328

Legal entity responsible for the study

AstraZeneca Pharmaceuticals LP

Funding

AstraZeneca Pharmaceuticals LP

Disclosure

D. Hong, G. Falchook, W. Harb, J.S. Wang: Research funding for clinical trials from AstraZeneca. C.E. Cook: AstraZeneca employee and stock holder. P. Lyne, P. McCoon, M. Mehta, P. Mitchell, M. Scott, G.M. Mugundu: Employee of AstraZeneca Pharmaceuticals LP.