Year: 2019
Type: article
Study design: Study Protocol
Abstract: Background: Standard initial treatment of indolent B-cell non-Hodgkin lymphoma (iB-NHL) includes intravenous or subcutaneous treatment requiring regular infusion center appointments. These can be burdensome, especially for patients living remotely from a cancer care facility. Furthermore, most patients with iB-NHL will have survival comparable to age matched controls. Thus, therapies that are sufficiently effective and minimally toxic while being maximally convenient are sought. Ixazomib, an orally bioavailable proteasome inhibitor, showed promising activity in a single study that included a small number of patients with relapsed/refractory iB-NHL (Assouline et al., 2014). As the maximum activity of a therapy is typically in the treatment-naïve setting, we designed a frontline "window" study to assess the potential ceiling of activity of ixazomib monotherapy in iB-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 one of the following iB-NHL: follicular lymphoma, marginal zone lymphoma, mantle cell lymphoma, chronic lymphocytic leukemia / small lymphocytic lymphoma, or Waldenstrom's macroglobulinemia / lymphoplasmacytic lymphoma. Additional eligibility criteria include a clinical indication for treatment, an Eastern Cooperative Oncology Group performance status of ≤2, and having received no prior standard 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. Ixazomib continues concurrently with rituximab and thereafter. Addition of rituximab is included to assure that all patients receive a standard therapy as part of their initial treatment. The primary endpoint is investigator-assessed response rate performed every 2 cycles. The null hypothesis that the true response rate is ≤40% will be tested against the alternative hypothesis that the true response rate is ≥60% with a type I error rate of 8% and a power of 85%, requiring an overall response rate of ≥19 of 36 to conclude promising efficacy. Secondary endpoints include duration of response, progression free survival, time to next treatment, and safety / tolerability. Tumor tissue is being collected for gene expression profiling using the NanoString platform and immunohistochemical evaluation of molecular pathways associated with proteasome inhibition. The study is supported by Takeda Oncology. Keywords: non-Hodgkin lymphoma (NHL). Disclosures: Graf, S: Research Funding: TG Therapeutics, Acerta Pharma, BeiGene. Lynch, R: Research Funding: TG Therapeutics, Rhizen Pharmaceuticals, Incyte, Takeda, Juno Therapeutics. Smith, S: Consultant Advisory Role: Astrazeneca, Merck Sharp and Dohme Corp.; Research Funding: Acerta Pharma BV, Astrazeneca, Ayala (spouse), Bristol Myers Squibb (spouse), De Novo Biopharma, Genentech, Ignyta (spouse), Incyte Corporation, Merck Sharp and Dohme Corp., Pharmacyclics, Portola Pharmaceuticals, Seattle Genetics. Shadman, M: Consultant Advisory Role: Abbvie, Genentech, Sound Biologics, Verastem, ADC Therapeutics, Atara Biotherapeutics; Research Funding: Mustang Biopharma, Celgene, Pharmacyclics, Gilead, Genentech, Abbvie, TG Therapeutics, Beigene, Acerta Pharma, Merck. Cassaday, R: Employment Leadership Position: Seattle Genetics (spouse); Consultant Advisory Role: Amgen, Pfizer; Stock Ownership: Seattle Genetics (spouse); Research Funding: Amgen, Incyte, Kite/Gilead, Merck, Pfizer. Gopal, A: Consultant Advisory Role: Seattle Genetics, Pfizer, Janssen, Gilead, Spectrum, Amgen, Incyte; Honoraria: Aptevo, BRIM Bio, Seattle Genetics, Sanofi; Research Funding: Teva, Bristol-Myers Squibb, Merck, Takeda, TG Therapeutics, Effector.
Source: Hematological Oncology
DOI: 10.1002/hon.18_2632
Language: English
Subfield: Genetics (clinical)
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W2949600157