Efficacy and Safety of SNX-5422 Added to an Established Dose of Ibrutinib in CLL

• ClinicalTrials.gov Identifier: NCT02973399
• Recruitment Status: Terminated
• First Posted: November 25, 2016
• Last Update Posted: February 22, 2019
• Sponsor: Esanex Inc.
• Information provided by (Responsible Party): Esanex Inc.

Study Description

Brief Summary:

SNX-5422 is a prodrug of SNX-2112, a potent, highly selective, small molecule inhibitor of the molecular chaperone heat shock protein 90 (HSP90). Hsp90 inhibitors may overcome ibrutinib resistance in Mantle cell lymphomas and this study will investigate whether the addition of SNX-5422 to an established dose of ibrutinib will provide clinical response in subjects who have residual disease, but have not progressed on ibrutinib after 18 months of monotherapy, and/or prevents or delays disease progression of subjects with CLL.

Condition or disease	Intervention/treatment	Phase
Cancer	Drug: SNX-5422 plus ibrutinib	Phase 1

Detailed Description:

Chronic lymphocytic leukemia (CLL) is the most prevalent leukemia in adults and is not considered curable outside of allogeneic stem cell transplantation. Significant advances have been made in the therapy, notably with the introduction of the Bruton's tyrosine kinase (BTK) inhibitor ibrutinib.

While response to ibrutinib has been high with therapy well-tolerated overall, some patients have relapsed while others have been taken off therapy for toxicity or other reasons. In addition, although remissions are durable in many patients, very few patients achieve a complete response (CR), and minimal residual disease (MRD) negativity on single agent ibrutinib has not been reported. Since it is known that for chemoimmunotherapy as well as targeted therapies such as venetoclax that attainment of a CR is associated with longer progression free survival (PFS), it is likely that deepening responses associated with ibrutinib will result in more durable remissions.

Relapse in CLL can be mediated by at least two separate mechanisms. One is by mutations in BTK, the other is through a variety of mutations in the immediate downstream target of BTK, PLCγ2. SNX-5422 is a prodrug of SNX-2112, a potent, highly selective, small molecule inhibitor of the molecular chaperone heat shock protein 90 (HSP90). Hsp90 inhibitors may overcome ibrutinib resistance in Mantle cell lymphomas and this study will investigate whether the addition of SNX-5422 to an established dose of ibrutinib will provide clinical response in subjects who have residual disease, but have not progressed on ibrutinib after 18 months of monotherapy.

Subjects will receive SNX-5422 (56 mg/m2) in the morning once every other day for 21 days (11 doses), followed by a 7-day drug-free period. Subjects will continue to receive daily oral ibrutinib at their established dose level in the afternoon

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 5 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 1, Open-label Study of SNX-5422 Added to Ibrutinib in Chronic Lymphocytic Leukemia Subjects With Residual Disease
• Actual Study Start Date: February 7, 2017
• Actual Primary Completion Date: December 4, 2018
• Actual Study Completion Date: February 4, 2019

Arms and Interventions

Arm

Intervention/treatment

Experimental: SNX-5422 plus ibrutinib; Open-label administration of SNX-5422 capsules dosed in the morning once every other day for 21 days (11 doses) followed by a 7 day drug free period and daily with the established ibrutinib dose for 28 days of a 28-days cycle. Subjects will repeat the 28-day schedule for 2 cycles after a CR or until the cancer progresses or the subject is unable to tolerate the therapy

Drug: SNX-5422 plus ibrutinib; SNX-5422 capsule(s) dosed every other day for 21 days out of a 28-day treatment cycle to a total dose of 56 mg/m2 SNX-5422. Subjects will self-administer daily oral ibrutinib in the afternoon at least 8 hours apart from SNX-5422 for 28 days of each cycle.; Other Name: Imbruvica

Outcome Measures

Primary Outcome Measures :

1. Efficacy of the combination of SNX-5422 and ibrutinib [ Time Frame: 6 months ]
   Proportion of subjects obtaining a complete response at the end of 6 SNX-5422 treatment cycles

Secondary Outcome Measures :

1. Number of subjects reporting adverse events [ Time Frame: Day 28 of each 4 week cycle from randomization up to 52 weeks ]
   Frequency and severity of adverse events
2. Complete response at 12 months [ Time Frame: 12 months ]
   Proportion of subjects obtaining a complete response at the end of 6 SNX-5422 treatment cycles
3. Improved Clinical Status [ Time Frame: 6 months ]
   Proportion of subjects obtaining improvement in clinical status (i.e., Stable Disease becoming Partial Response) at the end of 6 SNX-5422 treatment cycles
4. Progression free survival of patients receiving ibrutinib plus SNX-5422 [ Time Frame: Up to 52 weeks ]
   Elapsed time for each subject from randomization to continued survival up to 52 weeks

Other Outcome Measures:

1. BTK Mutation Level [ Time Frame: 6 and 12 months ]
   Change from baseline in percent of CLL cells with Bruton's Tyrosine Kinase mutations at the end of 6 and 12 treatment cycles

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Males or non-pregnant, non-breastfeeding females 18 years-of-age or older
• A diagnosis of CLL as defined by IWCLL 2008 criteria and currently on treatment with ibrutinib for at least 18 months with residual disease and without evidence of disease progression.
• No more than 4 prior lines of anti leukemia therapy (not including ibrutinib)
• Life expectancy of at least 9 months
• Karnofsky performance score 70
• Adequate baseline laboratory assessments
• Signed informed consent form
• Recovered from toxicities of previous anticancer therapy to CTCAE Grade ≤ 1
• Subjects with reproductive capability must agree to practice adequate contraception methods.

Exclusion Criteria:

• Subjects experiencing toxicity with ibrutinib
• Prior treatment with any Hsp90 inhibitor.
• Major surgery or significant traumatic injury within 4 weeks of starting study treatment.
• Conventional chemotherapy or radiation within 4 weeks.
• The need for treatment with medications with clinically-relevant metabolism by the cytochrome P450 (CYP) 3A4 isoenzyme within 3 hours before or after administration of SNX-5422
• Screening ECG QTc interval 470 msec for females, 450 msec for males.
• At increased risk for developing prolonged QT interval unless corrected to within normal limits prior to first dose of SNX-5422
• Patients with chronic diarrhea or with Grade 2 or greater diarrhea despite appropriate medical management.
• Gastrointestinal diseases or conditions that could affect drug absorption or could alter the assessment of safety
• History of documented adrenal dysfunction not due to malignancy.
• History of chronic liver disease.
• Active hepatitis A or B.
• Current alcohol dependence or drug abuse.
• Use of an investigational treatment (except for ibrutinib) from 30 days prior to the first dose
• Glaucoma, retinitis pigmentosa, macular degeneration, or any retinal changes detected by ophthalmological examination that are considered clinically important by examiner.
• Psychological or social reasons that would hinder or prevent compliance with the requirements of the protocol or compromise the informed consent process.

Contacts and Locations

Locations

United States, New York

Weill Cornell Medical College

New York, New York, United States, 10065

United States, Ohio

Wexner Medical Center, Ohio State University

Columbus, Ohio, United States, 43210

Sponsors and Collaborators

Esanex Inc.

More Information

• Responsible Party: Esanex Inc.
• ClinicalTrials.gov Identifier: NCT02973399
• Other Study ID Numbers: SNX-5422-CLN1-012
• First Posted: November 25, 2016
• Last Update Posted: February 22, 2019
• Last Verified: February 2019

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Esanex Inc.:

CLL; Leukemia, Chronic Lymphocytic; Hsp90; Ibrutinib

Additional relevant MeSH terms:

Ibrutinib; Tyrosine Kinase Inhibitors; Protein Kinase Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action