Clinical trial NCT02383368: A Dose Escalation and Expansion Study of ASP4132 to Subjects With Advanced Refractory Tumors and Lymphoma
Official title: An Open-Label, Dose-Escalation/Expansion Phase 1 Study of ASP4132 Given Orally to Patients With Advanced Refractory Solid Tumors and Lymphoma
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Lymphoma
Refractory Solid Tumors
Advanced Cancer
Keywords: Pharmacokinetics
ASP4132
Lymphoma
Refractory Solid Tumors
Lead sponsor: Astellas Pharma Inc
Sponsor class: INDUSTRY
First posted: 2015-03-09
Enrollment: 39
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to evaluate the safety and tolerability of ASP4132 and to determine the maximum tolerated dose and recommended phase 2 dose of ASP4132. The study will also determine the pharmacokinetics (PK) of ASP4132 and evaluate the preliminary antitumor activity.

Detailed description: The study consists of two parts and these will be conducted sequentially: Part 1 (dose escalation) and Part 2 (dose expansion). Subjects will participate in Part 1 or Part 2.

Eligibility criteria: Inclusion Criteria:

* Subject has a life expectancy of more than 3 months
* Subject agrees not to participate in another interventional study while on treatment.
* Subject has an Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2.
* Female subject must be either:

  1. Of non-child bearing potential:

     * post-menopausal (defined as at least 1 year without any menses) prior to Screening,
     * or, documented surgically sterile or status post hysterectomy
  2. Or, if of childbearing potential,

     * agree not to try to become pregnant during the study and for 90 days after the final study drug administration;
     * if heterosexually active must use two forms of birth control
* Male subject and their female spouse/partners who are of childbearing potential must be using highly effective contraception consisting of two forms of birth control (one of which must be a barrier method) starting at Screening and continue throughout the study period and for 90 days after the final study drug administration.
* Subject must have advanced and/or metastatic, histologically or cytologically documented cancer or lymphomas, for whom there is no available standard therapy shown to provide clinical benefit.

Exclusion Criteria:

* Subject has absolute neutrophil count \< 1000/μL, platelet count \< 75,000/μL, and hemoglobin \< 8 g/dL (\< 5 mmol/L) at Screening
* Subject has total serum bilirubin ≥1.5 times the upper limit of normal (ULN),serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) \> 3 times ULN, or albumin ≤ 3.0 g/dL at Screening.
* Subject has any abnormalities in serum sodium, potassium, chloride, calcium and magnesium levels ≥ Grade 2 at screening (CTCAE Version 4.03).
* Subject has a known elevation in serum lactate at screening ˃ 2x institutional ULN
* Subject has an estimated glomerular filtration rate (eGFr) of \< 60ml/min as calculated by the modification of diet Renal disease (MDRD) Equation.
* Subject with a QTcF of \> 450 msec in male subjects and \> 470 msec in female subjects on the screening 12 lead ECG.
* Subject has Neuropathy ≥ Grade 2 at Screening.
* Subject has Type 1 Diabetes Mellitus or Type 2 Diabetes Mellitus and currently being treated with insulin or sulfonylureas.
* Subject has concomitant active second malignancies unless remission was achieved at least 3 years prior to study entry and subject is no longer on therapy for the malignancy.
* Subject has a significant cardiovascular disease
* Subject has a known history of acute or chronic hepatitis B (HBV), HIV or hepatitis C (HCV) infection.
* Subject has serious/active bacterial, viral or fungal infection requiring systemic treatment.
* Subject has significant gastrointestinal abnormalities, including ulcerative colitis, chronic diarrhea associated with intestinal malabsorption, Crohn's disease, and/or prior surgical procedures affecting absorption or requirement for intravenous (IV) alimentation.
* Subject has active central nervous system (CNS) metastases not controlled by prior surgery or radiotherapy (subjects must be off steroids). Subjects with signs or symptoms suggestive of brain metastasis are not eligible unless brain metastases are ruled out by brain MRI/CT.
* Subject has concurrent severe or uncontrolled medical disease or organ system dysfunction which, in the opinion of the Investigators, would limit life expectancy to \< 3 months.
* Subject has psychiatric disorder or altered mental status that would preclude an understanding of the informed consent process and/or completion of the necessary study procedures.
* Subject has difficulty swallowing large pills.
* Subject currently being treated with biguanides or other agents known to increase risk of lactic acidosis.
* Subject has unavoidable concomitant treatment with any drug known for causing Torsades de Pointes.
* Subject has had radiotherapy or surgery within the 4 weeks prior to treatment with ASP4132.
* Subject has not discontinued all previous systemic therapies for cancer including chemotherapy, immunotherapy, or biological therapies for at least 14 days prior to the initiation of ASP4132.
* Subject has not fully recovered from the acute toxicities (except alopecia) of any prior anti-cancer therapy.
* Subject requiring concomitant use of strong CYP3A4 inhibitors or inducers.

Primary outcomes:
measure: Safety as assessed by adverse events
timeFrame: up to 39 months
measure: Safety as assessed by clinical laboratory tests
timeFrame: up to 39 months
measure: Safety as assessed by vital signs
timeFrame: up to 39 months
measure: Safety as assessed by electrocardiograms (ECG)
timeFrame: up to 39 months
Secondary outcomes:
measure: Objective response rate to ASP4132
timeFrame: Week 16
measure: Duration of response to ASP4132
timeFrame: Week 16
measure: Disease control rate to ASP4132
timeFrame: Week 16
measure: Maximum concentration (Cmax) of ASP4132
timeFrame: up to 43 days
measure: Time of the maximum concentration (Tmax) of ASP4132
timeFrame: up to 43 days
measure: Area under the concentration-time curve from time of dosing to the last measurable concentration (AUClast) of ASP4132
timeFrame: up to 43 days
measure: AUC from the time of dosing to 24 hours (AUC24) of ASP4132
timeFrame: up to 43 days
measure: AUC from the time of dosing extrapolated to time infinity (AUCinf) of ASP4132
timeFrame: up to 43 days
measure: Apparent terminal elimination half-life (T1/2) of ASP4132
timeFrame: up to 43 days
measure: Accumulation ratio of ASP4132
timeFrame: up to 43 days
measure: Apparent total systemic clearance after single or multiple extravascular dosing (CL/F) of ASP4132
timeFrame: up to 43 days
measure: Apparent volume of distribution during the terminal elimination phase after single or multiple extravascular dosing (Vz/F) of ASP4132
timeFrame: up to 43 days
measure: Progression-free survival
timeFrame: up to 39 months
Other outcomes:
Locations:
city: New Haven
country: United States
facility: Site US10001
state: Connecticut
city: Chicago
country: United States
facility: Site US10004
state: Illinois
city: Rochester
country: United States
facility: Site US10002
state: Minnesota
city: Houston
country: United States
facility: Site US10003
state: Texas
city: Fairfax
country: United States
facility: Site US10005
state: Virginia
Study officials:
affiliation: Astellas Pharma Global Development, Inc.
name: Medical Director
role: STUDY_DIRECTOR
References:
citation: Janku F, LoRusso P, Mansfield AS, Nanda R, Spira A, Wang T, Melhem-Bertrandt A, Sugg J, Ball HA. First-in-human evaluation of the novel mitochondrial complex I inhibitor ASP4132 for treatment of cancer. Invest New Drugs. 2021 Oct;39(5):1348-1356. doi: 10.1007/s10637-021-01112-7. Epub 2021 Apr 8.