Cancer
Conditions
Keywords
CLL, Leukemia, Chronic Lymphocytic, Hsp90, Ibrutinib
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.
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
Interventions
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.
Sponsors
Esanex Inc.
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Efficacy of the combination of SNX-5422 and ibrutinib | 6 months | Proportion of subjects obtaining a complete response at the end of 6 SNX-5422 treatment cycles |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of subjects reporting adverse events | Day 28 of each 4 week cycle from randomization up to 52 weeks | Frequency and severity of adverse events |
| Complete response at 12 months | 12 months | Proportion of subjects obtaining a complete response at the end of 6 SNX-5422 treatment cycles |
| Improved Clinical Status | 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 |
| Progression free survival of patients receiving ibrutinib plus SNX-5422 | Up to 52 weeks | Elapsed time for each subject from randomization to continued survival up to 52 weeks |
Other
| Measure | Time frame | Description |
|---|---|---|
| BTK Mutation Level | 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 |
Countries
United States
Outcome results
None listed