A Window Study of Ixazomib in Untreated B-NHL
Authors: Graf Solomon A. , Lynch Ryan C. , Ujjani Chaitra S. , Coffey David G. , Cowan Andrew J. , Smith Stephen D. , Shadman Mazyar , Warren Edus H. , Libby Edward N. , Godwin Colin D. , Cassaday Ryan D. , Gooley Ted A , Fromm Jonathan R. , Gopal Ajay K. 
Published: November 2019

Background: Window of opportunity studies are rarely conducted in lymphoma, but permit evaluation of novel therapies before resistance mechanisms emerge. Identification of a minimum acceptable response rate in the first-line setting may expedite drug development and is most attractive for testing relatively nontoxic, oral targeted agents that may offer substantial logistical and clinical benefits (1). Ixazomib, an orally bioavailable proteasome inhibitor, showed promising activity in a single small study that included relapsed/refractory indolent B-cell NHL (i-NHL) (2). We designed a frontline "window" study to assess the activity of ixazomib monotherapy in patients with i-NHL.
Methods: This single-arm, open-label investigator-initiated phase II trial (NCT 02339922) is being conducted at the University of Washington / Fred Hutch Cancer Research Center. Patients must have a diagnosis of i-NHL and a clinical indication for treatment per NCCN guidelines. Other criteria are ECOG ≤ 2, and no prior systemic anti-neoplastic treatment except in cases of mucosa-associated marginal zone lymphoma relapsed after or refractory to antibiotics.
Ixazomib is administered at 4 mg orally once a week on consecutive 28-day cycles until disease progression or unacceptable toxicity. The window period closes after 6 cycles, with four doses of weekly rituximab added during the 7th cycle to test the safety and efficacy of this combination.
The primary endpoint is investigator-assessed response rate performed every 2 cycles. An overall response rate of ≥ 19 of 36 is required to conclude promising efficacy. Secondary endpoints include duration of response, progression free survival, time to next treatment, and safety / tolerability. Correlative studies are being performed on tumor tissue samples collected pre-treatment and paired with biopsies obtained, as able, within 2 months after initiation of ixazomib and with clinically suspected disease progression to gain insight into potential molecular predictors of response. Correlates under investigation include gene expression profiling using the Nanostring platform and immunohistochemical evaluation of pathways associated with lymphoma proliferation and proteasome inhibition.
The study opened in May 2016 and as of June 2019, 32 patients were screened. Of 23 patients treated the median age is 64 (range 41 to 85) and 15 (65%) are male. Fifteen (65%) patients had follicular lymphoma, 4 (17%) mantle cell lymphoma, 3 (13%) marginal zone lymphoma, and 1 (4%) chronic lymphocytic leukemia. No unexpected toxicities have emerged to date. The study is supported by Takeda Oncology. Glimelius B, Lahn M. Window-of-opportunity trials to evaluate clinical activity of new molecular entities in oncology. Ann Oncol. 2011;22(8):1717-25.Assouline SE, Chang J, Cheson BD, Rifkin R, Hamburg S, Reyes R, et al. Phase 1 dose-escalation study of IV ixazomib, an investigational proteasome inhibitor, in patients with relapsed/refractory lymphoma. Blood Cancer J. 2014;4:e251.

Disclosures
Graf: BeiGene: Research Funding; AstraZeneca: Research Funding; TG Therapeutics: Research Funding. Lynch:Johnson Graffe Keay Moniz & Wick LLP: Consultancy; Incyte Corporation: Research Funding; Juno Therapeutics: Research Funding; T.G. Therapeutics: Research Funding; Rhizen Pharmaceuticals S.A: Research Funding; Takeda Pharmaceuticals: Research Funding. Ujjani:Gilead: Consultancy; Astrazeneca: Consultancy; Atara: Consultancy; Genentech: Honoraria; AbbVie: Honoraria, Research Funding; Pharmacyclics: Honoraria; PCYC: Research Funding. Cowan:Abbvie: Research Funding; Celgene: Consultancy, Research Funding; Sanofi: Consultancy; Cellectar: Consultancy; Juno: Research Funding; Janssen: Consultancy, Research Funding. Smith:Pharmacyclics: Research Funding; Seattle Genetics: Research Funding; Portola Pharmaceuticals: Research Funding; Genentech: Research Funding; Ayala (spouse): Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding; Denovo Biopharma: Research Funding; Ignyta (spouse): Research Funding; Merck Sharp & Dohme Corp: Consultancy, Research Funding; Incyte Corporation: Research Funding; Acerta Pharma BV: Research Funding; Bristol-Myers Squibb (spouse): Research Funding. Shadman:BeiGene: Research Funding; Sound Biologics: Consultancy; Celgene: Research Funding; Gilead: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; TG Therapeutic: Research Funding; Sunesis: Research Funding; Astra Zeneca: Consultancy; Atara Biotherapeutics: Consultancy; Mustang Bio: Research Funding; ADC Therapeutics: Consultancy; Verastem: Consultancy; AbbVie: Consultancy, Research Funding; Acerta Pharma: Research Funding. Libby:Alnylam: Consultancy; Abbvie: Consultancy; Pharmacyclics and Janssen: Consultancy; Akcea: Consultancy. Cassaday:Amgen: Consultancy, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Incyte: Research Funding; Kite/Gilead: Research Funding; Merck: Research Funding; Seattle Genetics: Research Funding; Seattle Genetics: Other: Spouse's disclosure: employment, stock and other ownership interests. Fromm:Merck, Inc.: Research Funding. Gopal:Teva, Bristol-Myers Squibb, Merck, Takeda, Seattle Genetics, Pfizer, Janssen, Takeda, and Effector: Research Funding; Seattle Genetics, Pfizer, Janssen, Gilead, Sanofi, Spectrum, Amgen, Aptevo, BRIM bio, Acerta, I-Mab-pharma, Takeda, Compliment, Asana Bio, and Incyte: Honoraria; Seattle Genetics, Pfizer, Janssen, Gilead, Sanofi, Spectrum, Amgen, Aptevo, BRIM bio, Acerta, I-Mab-pharma, Takeda, Compliment, Asana Bio, and Incyte.: Consultancy.

OffLabel Disclosure:
Ixazomib is not approved for use in indolent B-NHL.