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Vecabrutinib (SNS-062) Clinical Trials

Phase 1b/2: Single Agent SNS-062
Status: Recruiting
Focus: Safety, PK, PD, and Antitumor Activity in B Lymphoid Cancers

SNS-062 is a non-covalent BTK inhibitor being developed as a therapy for B-cellmalignancies. SNS-062 does not interact with the cysteine residue, C481, required for clinical activity by ibrutinib and other covalent BTK inhibitors. Mutation of this critical cysteine to serine is a resistance mechanism in patients treated with the covalent BTK inhibitors. As a potent inhibitor of both wild-type and C481S BTK, SNS-062 may overcome this resistance mechanism.

A Phase 1b/2, open-label, sequential-group, dose-escalation and cohort-expansion study evaluating the safety, pharmacokinetics, pharmacodynamics, and antitumor activity of SNS-062 is currently ongoing.

The Phase 1b (Dose escalation) portion of the study will evaluate the safety and pharmacology of a range of SNS-062 dose levels administered to subjects with previously treated B-lymphoid malignancies, including: chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), lymphoplasmacytoid lymphoma/Waldenström's macroglobulinemia (LPL/WM), mantle cell lymphoma (MCL), and other lymphomas.

The Phase 2 (Cohort Expansion) portion of the study provides cohort expansion to further explore the clinical activity, safety, and pharmacology of SNS-062 monotherapy at the dose selected in the Phase 1b portion.

The unique identifier for this study on ClinicalTrials.gov is NCT03037645.

Phase 1: Single agent SNS-062 in Healthy Volunteers
Status: Closed to new recruitment
Focus: Safety, Pharmacokinetics, Pharmacodynamics, Food Effects, and Drug-Drug Interactions in Healthy Volunteers

Oral SNS-062 administration was evaluated in healthy subjects in a Phase 1a, single-dose, double-blind, placebo-controlled, dose-ranging clinical trial (EudraCT 2016-000180-16). The study was conducted in 3 stages: Stage 1 was a dose escalation stage with doses of 50, 100, 200, and 300 mg (N=32: 6 subjects/cohort; 8 subjects received placebo). Analyses of PK and pharmacodynamic (inhibition of BTK phosphorylation) data, and PK simulations indicated that twice daily dosing of SNS-062 at dose levels of 100 mg/dose could result in concentrations sufficient to induce adequate and prolonged inhibition of the enzyme for clinical activity. SNS-062 was well tolerated.

Vosaroxin Clinical Trials

Investigator Sponsored Trials

Phase 2: VITAL: Vosaroxin in combination with cytarabine in patients with untreated AML
Sponsor: Vanderbilt University Medical Center
Status: Enrolling
Focus: Frontline AML
Vosaroxin, a first-in-class anticancer quinolone derivative, administered in combination with intermediate dose cytarabine (IDAC) in relapsed/refractory AML pts has demonstrated the ability to significantly improve CR rates compared to IDAC alone, and has a well described safety profile. As vosaroxin ± cytarabine has been successfully administered and tolerated in both AML pts of advanced age (≥ 60 years) the purpose of this study is to investigate the combination of infusional cytarabine with vosaroxin (“7+V”) in newly diagnosed AML.

The unique identifier for this study on ClinicalTrials.gov is NCT02658487.

Phase 1/2: Vosaroxin in combination with HiDAC vs, HiDAC as Consolidation regimen
Sponsor: ALFA/FILO
Status: Enrolling
Focus: Frontline AML and High-Risk MDS
The BIG study is a randomized phase 2-3 study of vosaroxin plus intermediate/High dose Cytarabine (IHDAC) versus IHDAC in patients with previously untreated intermediate risk AML. The vosaroxin arm is nested in R2, evaluating the benefit of vosaroxin added to IDAC as a post-induction therapy (control of residual disease) in young AML intermediate risk patients in first line

The EudraCT Number for this study is 2014-000699-24

Phase 1/2: Vosaroxin in combination with decitabine
Sponsor: University of Texas MD Anderson Cancer Center Status: Closed
Focus: Frontline AML and High-Risk MDS
In July 2013, we announced the initiation of an investigator-sponsored trial of vosaroxin in combination with decitabine in older patients with previously untreated AML and high-risk MDS. The Phase 1/2 trial was conducted at the University of Texas MD Anderson Cancer Center under the direction of Naval Daver, M.D., Assistant Professor, and Farhad Ravandi, M.D., Professor of Medicine and a principal investigator in the VALOR trial. The primary endpoints of the Phase 1 cohort of the study were to determine the safety, maximum tolerated dose, or MTD, and dose limiting toxicity, or DLT, of vosaroxin in combination with decitabine in patients with high-risk MDS or AML who are elderly and/or unable or unwilling to receive standard cytarabine plus anthracycline based chemotherapy. The primary endpoint of the Phase 2 cohort of the study was to determine the efficacy of the combination based on achievement of CR, and CR with incomplete blood count recovery, or CRi. Secondary endpoints include safety, CR duration, leukemia-free survival, and overall survival. The results from the study were published in Haematologica in July 2017

The initial 22 patients on study received vosaroxin 90 mg/m2 on Days 1 and 4 with decitabine 20 mg/m2 Days 1-5 every 4-6 weeks for up to 7 cycles. Due to high incidence of mucositis the subsequent 43 patients received vosaroxin 70 mg/m2 Days 1 and 4. Sixty-five patients with median age 69 years (range 60-78) were evaluable. The overall response rate (ORR) was 74% including complete remission (CR) in 31 (48%), complete remission with incomplete platelet recovery (CRp) in 11 (17%), and complete remission with incomplete count recovery (CRi) in 6 (9%). The 70 mg/m2 induction dose of vosaroxin was associated with similar ORR (74% versus 73%) and CR rate (51% versus 41%), reduced incidence of mucositis (30% versus 59%), reduced 8-week mortality (9% versus 23%), and improved median overall survival (OS) (14.6 months versus 5.5 months). MRD-negative status by multiparametric flow-cytometry at response (+/- 3 months) was achieved in 21 of 39 (54%) evaluable responders and was associated with improved median OS (34.0 months versus 8.3 months, P=0.023). The combination of vosaroxin with decitabine is effective and well tolerated at 70 mg/m2 and warrants randomized prospective evaluation.

Sunesis Sponsored Clinical Trials

Phase 3: VALOR (vosaroxin in combination with cytarabine)
Status: Complete
Focus: First Relapsed/Refractory AML

Sunesis' most advanced program is QINPREZO™ (vosaroxin), our product candidate for the potential treatment of acute myeloid leukemia ("AML"). Vosaroxin is an anticancer quinolone derivative ("AQD") – a class of compounds that has not been used previously for the treatment of cancer.

The VALOR study failed to meet the primary endpoint of a significant difference in Overall Survival (OS) between the treatment arms in the primary analysis by a narrow margin (n=711 patients, p=.06). The clinical benefit in VALOR was driven by activity seen in the 356 patient subgroup ≥ 60 years of age. In this subgroup, a significant benefit in OS (2.1 month increase) was observed for the vosaroxin/cytarabine arm versus the placebo/cytarabine arm (HR = 0.75, one-sided p = 0.0015). The benefit observed in OS was supported by the results of the secondary and tertiary endpoint analyses. The complete response rate for patients ≥ 60 years of age in the vosaroxin/cytarabine arm was more than double that in the placebo/cytarabine arm (31.9% versus 13.8%; two-sided p < 0.0001). The leukemia free survival data showed a numeric advantage for the vosaroxin/cytarabine arm in durability of response for patients aged ≥ 60 years, and event free survival was significantly prolonged (HR = 0.61, one-sided p < 0.0001).

In July 2015, we met with the U.S. Food and Drug Administration (FDA) to discuss a potential regulatory filing in the United States. In June 2015, we met separately with our Rapporteur and Co-Rapporteur, who are two appointed members of the European Medicines Agency (EMA)'s Committee of Human Medicinal Products. Based upon feedback from the EMA meetings, we filed a Marketing Authorization Application in December 2015. Subsequently, both the FDA and EMA have recommended that we provide additional clinical evidence prior to any regulatory filing in the U.S. or further regulatory filings in the EU. As a result, we will evaluate regulatory and clinical strategies with the goal of gaining future marketing approval in both the U.S. and EU.

The unique identifier for this study on ClinicalTrials.gov is NCT01191801.

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