Safety,Tolerability and MTD KA2507 (HDAC6 Inhibitor) in Patients With Solid Tumours

NCT03008018 | Completed Phase 1 FDA Drug

• 1 other identifier: KTP-003
• Study Type: interventional
• Target: 20
• Locations: 1 country
• Sites: 1

Brief Summary

The aim of the study is to evaluate the safety/tolerability, pharmacokinetic, and pharmaco-dynamic effects of KA2507 and establish the maximum tolerated dose (MTD). Patients with PD-L1 expressing solid tumors which have relapsed or are refractory to prior treatment will be eligible to participate in this study. Following completion of the multiple ascending dose study, the protocol may be amended to include expansion cohorts in patients with melanoma and/or other solid tumors.

Conditions

Solid Tumor, Adult

Outcome Measures

Primary Outcomes (1)

• The occurrence of dose limiting toxicity

  1\. Any event with possible or probable relationship to study drug occurring up to day 28 from the start of treatment as assessed using the National Cancers Institutes Common Terminology Criteria for Adverse events version 4.03 therapy.

  28 days

Secondary Outcomes (7)

• Concentration of KA2507 in plasma over time (hours) post dosing

  24 weeks

• Concentration of KA2507 in urine over time (hours) post dosing

  24 weeks

• Blood concentration of histone acetylation during KA2507 treatment

  24 weeks

• Blood concentration of tubulin during KA2507 treatment

  24 weeks

• Number of Participants With Abnormal Laboratory Values and/or Adverse Events That Are Related to Treatment

  24 weeks

Other Outcomes (2)

• Concentration of PD-L1 expression in tumor tissue

  24 weeks

• Concentration of MHC-1 expression in tumor tissue

  24 weeks

Study Arms (1)

KA2507 (HDAC6 inhibitor)

OTHER

This is a single arm dose escalating study. Patients will be treated with open label KA2507 (HDAC6 inhibitor) capsules.

Drug: KA2507

Interventions

KA2507 DRUG

KA2507, an orally-active new chemical entity, is a potent and selective inhibitor of the HDAC6 enzyme, with potential clinical utility in the treatment of melanoma and other solid tumors. KA2507 has been shown to display potent in vitro activity in a range of cancer cell lines, including melanoma cell lines. KA2507 exerts potent in vivo efficacy in a syngeneic model of B16 melanoma. Here, the combination of the agent's direct tumor growth inhibition and metastasis suppression, coupled with its immunotherapeutic activity - demonstrated by decreased expression of STAT-3 and PD-L1 and increased expression of acetylated tubulin, gp100 and MHC Class I in tumors - have been observed.

Also known as: HDAC6 Inhibitor, HDAC6i

KA2507 (HDAC6 inhibitor)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age ≥18 years at the screening visit.
• Patients with histologically or cytologically documented, confirmed diagnosis of advanced malignancy, whose disease failed to respond to or progressed after standard therapy or they could not tolerate standard therapy.
• Measurable or evaluable disease according to RECIST v1.1.
• ECOG performance status of 0 or 1.
• Predicted life expectancy ≥12 weeks.
• For men and women of child-bearing potential, willing to use adequate contraception (i.e., latex condom, cervical cap, diaphragm, abstinence, etc.) for the entire duration of the study.
• \. If female, must be either postmenopausal, sterilised or, if sexually active, effectively practicing an acceptable method of contraception (either oral, parenteral, or implantable hormonal contraceptives, intrauterine device or barrier and spermicide). Subjects must agree to use adequate contraception during the study and for at least 12 weeks (or longer as per local requirement) after the last dose of study treatment.
• \. Male subjects agree to ensure that they or their female partner(s) use adequate contraception during the study and for at least 12 weeks (or longer as per local requirement) after the subject receives their last dose of study treatment.

You may not qualify if:

• Patients are not able to provide written informed consent to study participation
• Patients who have been treated with most recent radiotherapy, hormonal therapy, immunotherapy, chemotherapy or investigational drugs within ≤21 days or 5 half-lives (whichever is shorter) from enrolment (screening), and/or who have any unresolved NCI Common Terminology Criteria of Adverse Events (CTCAE) v4.03 \> Grade 1 treatment-related side effect (with the exception of alopecia).
• Patient has anemia due to HbS or HbC disease, alpha or beta thalassaemia
• Patient has Glucose-6-phosphate deficiency
• Patient has known or suspected history of cytochrome b5-MetHb-reductase pathway deficiency
• Persons of Navajo, Athabaska Alaskan or Siberian Yakutsk descent
• Patient has untreated severe hypothyroidism
• Patient has laboratory estimations indicating organ system dysfunction:
• Absolute neutrophil count (ANC) \<1.5 X 109/L
• Platelets \<100 X 109/L
• Hemoglobin \<9g/dL
• Total bilirubin \>1.5 mg/dL
• ALT and AST \>3.0 times the ULN if no liver involvement or \>5 times the ULN with liver involvement.
• Calculated creatinine clearance \<60mL/min estimated using the Cockcroft-Gault equation:
• Cockcroft-Gault equation: creatinine clearance = (140 - age in years) x (wt in kg)) x 1.23) / (serum creatinine in micromol/l) \[For women multiply the result of calculation by 0.85\].

Sponsors & Collaborators

• Karus Therapeutics Limited: lead

Study Sites (1)

M D Anderson

Houston, Texas, 77030, United States

Location

Related Publications (1)

• Tsimberidou AM, Beer PA, Cartwright CA, Haymaker C, Vo HH, Kiany S, Cecil ARL, Dow J, Haque K, Silva FA, Coe L, Berryman H, Bone EA, Nogueras-Gonzalez GM, Vining D, McElwaine-Johnn H, Wistuba II. Preclinical Development and First-in-Human Study of KA2507, a Selective and Potent Inhibitor of Histone Deacetylase 6, for Patients with Refractory Solid Tumors. Clin Cancer Res. 2021 Jul 1;27(13):3584-3594. doi: 10.1158/1078-0432.CCR-21-0238. Epub 2021 May 4.

  PMID: 33947698 DERIVED

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 21, 2016
• First Posted: January 2, 2017
• Study Start: August 7, 2017
• Primary Completion: June 10, 2020
• Study Completion: June 10, 2020
• Last Updated: August 19, 2020

Record last verified: 2020-08

Locations

US (1)