An Exploratory Study of the Safety and Efficacy of ACP-196 in Spontaneous Canine B-cell Lymphoma

Purpose of Study

This is an open-label, dose-escalation study evaluating the activity of ACP-196 in combination with ACP-319 given to dogs with B-cell lymphoma.

Background

BTK is a protein that is involved in cell signaling in B lymphocytes (white blood cells), B cell lymphoma, and other cells. It has been shown that in many B cell lymphomas, blocking the BTK protein can prevent growth of lymphoma cells and in many instances, cause death of these cells. Therefore, inhibitors of BTK hold great promise for treating B cell lymphomas and possibly other cancers. Ibrutinib is a first generation BTK inhibitor that has shown good effects in both humans and dogs with B cell lymphoma, and in humans is currently in late stage clinical trials heading for approval. ACP-196 is a novel second generation BTK inhibitor that has greater specificity for BTK, thereby limiting its side effects. It is well-absorbed after oral administration and has shown good activity in mouse models of lymphoma.

ACP-196 has been tested in normal dogs and was found to be safe at doses to be used in this clinical trial. Given the demonstrated activity of ibrutinib in dogs with B cell lymphoma, it is expected that ACP-196 will show good activity in this setting as well. ACP-319 is a novel PI3-kinase inhibitor that inhibits another protein in the B cell signaling pathway. Laboratory studies show that the combination of a BTK inhibitor and a PI3-kinase inhibitor has greater activity and efficacy than either agent alone.

Inclusion criteria

To qualify for enrollment for this study, dogs must:

  • Confirmed histologic or cytologic diagnosis of new or relapsed B-cell lymphoma (immunophenotype confirmed by immunohistochemistry, flow cytometry, or PARR).
  • Must be at least 1 year of age and ≥ 8 kg and ≤ 50 kg.
  • Have a nodal presentation (stage 2 or greater) with a minimum lymph nodes size of 2 cm in the longest dimension.
  • Adequate organ function as indicated by standard laboratory tests (complete blood count, serum biochemistry profile, urinalysis).
  • Owner must be able to orally administer drug according to designated schedule.
  • Owner must give informed consent.

Exclusion criteria

Dog will not qualify for this study if:

  • Has T-cell or null-cell immunophenotype lymphoma.
  • Received chemotherapy within 2 weeks of first dose.
  • Received radiation therapy within 2 weeks of first dose.
  • Has been administered corticosteroids within 72 hrs of first dose.
  • Less than 2 weeks from a major surgical procedure or use of any other investigational drug.
  • Has any serious systemic disorder incompatible with the study (at the discretion of the PIs).

Study Design

  • Patients will be screened for eligibility, if enrolled your dog will receive ACP-196 in combination with ACP-319 twice per day. Dose escalations are possible. Your dog will return weekly for the first 4 weeks, if your dog is responding to therapy you will return every 2 weeks thereafter until progressive disease is noted, a clinical toxicity occurs that precludes drug administration or if the principal investigator believes it is not in the best interest for your dog to continue receiving drug. Analysis for tumor response will be performed by direct tumor measurement or through the use of x-rays.
  • Additional tests to be performed include a blood draw to collect white blood cells for analysis, a pre-treatment lymph node biopsy and a fine needle aspiration of the lymph nodes before and 3 hrs after dosing on day 0 and before dosing on day 7 of the study.
  • Dogs enrolled in the pharmacokinetic portion of the study, on day 14 will stay in the hospital overnight so that blood samples can be drawn over 24 hours to assess how ACP-196/ACP-319 blood levels change during the course of the day. The total volume of blood involved in this collection is approximately 4 tablespoons. You will receive a credit of $150 for the treatment of your dog at the Veterinary Medical Center for participation in the overnight study.

Client Compensation

If deemed eligible, the sponsor will cover study associated costs for screening, exam fees, lab work and treatment of any side effects associated with treatment.
For the dogs participating in the pharmacokinetic portion of the study you will receive a $150 credit at the Veterinary Medical Center that can be used for additional treatment.

Contact Information

Please contact the Clinical Trials Office at the Veterinary Medical Center for more information about this study.