Clinical Trials /

Phase I, First-in-human Study of Oral TP-1287 in Patients With Advanced Solid Tumors

NCT03604783

Description:

TP-1287 is an oral phosphate prodrug of the CDK9 inhibitor, alvocidib. This is a Phase 1, open-label, dose-escalation, safety, pharmacokinetics, and pharmacodynamic study, with a purpose of determining the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of oral TP-1287 in patients with advanced metastatic or progressive solid tumors who are refractory to, or intolerant of, established therapy known to provide clinical benefit for their condition.

Related Conditions:
  • Malignant Solid Tumor
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Phase I, First-in-human Study of Oral TP-1287 in Patients With Advanced Solid Tumors
  • Official Title: A Phase I, First-in-human, Open-label, Dose Escalation, Safety, Pharmacokinetic, and Pharmacodynamic Study of Oral TP-1287 to Patients With Advanced Solid Tumors

Clinical Trial IDs

  • ORG STUDY ID: TP-1287-101
  • NCT ID: NCT03604783

Conditions

  • Advanced Solid Tumors

Interventions

DrugSynonymsArms
TP-1287Single Arm TP-1287

Purpose

TP-1287 is an oral phosphate prodrug of the CDK9 inhibitor, alvocidib. This is a Phase 1, open-label, dose-escalation, safety, pharmacokinetics, and pharmacodynamic study, with a purpose of determining the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of oral TP-1287 in patients with advanced metastatic or progressive solid tumors who are refractory to, or intolerant of, established therapy known to provide clinical benefit for their condition.

Detailed Description

      Primary Objective:

        -  To determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of
           oral TP-1287 in patients with advanced metastatic or progressive solid tumors who are
           refractory to, or intolerant of, established therapy known to provide clinical benefit
           for their condition.

        -  To establish the Recommended Phase 2 Dose (RP2D) for future studies with TP-1287

      Secondary Objectives:

        -  To establish the pharmacokinetics of orally administered TP-1287

        -  To observe patients for any evidence of antitumor activity of TP-1287 by objective
           radiographic assessment

        -  To study the pharmacodynamics of TP-1287 therapy
    

Trial Arms

NameTypeDescriptionInterventions
Single Arm TP-1287ExperimentalTP-1287 by oral administration
  • TP-1287

Eligibility Criteria

        Inclusion Criteria:

          1. Have a histologically confirmed diagnosis of advanced metastatic or progressive solid
             tumor excluding tumor types with rapid cell turnover, ie, small cell cancer (lung and
             extra pulmonary), inflammatory breast cancer (IBC), medulloblastoma, neuroblastoma and
             melanoma with extensive liver metastasis (greater than or equal to 50% of the liver
             involved; patients with melanoma and metastasis to less than 50% of the liver are
             eligible)

          2. Be refractory to, or intolerant of, established therapy known to provide clinical
             benefit for their condition.

          3. Have one or more tumors measurable or evaluable as outlined by modified Response
             Evaluation Criteria in Solid Tumors (RECIST) v1.1

          4. Have an Eastern Cooperative Oncology Group (ECOG) performance status of less than or
             equal to 1

          5. Have a life expectancy greater than or equal to 3 months

          6. Be greater than or equal to 18 years of age

          7. Have a negative pregnancy test (if female of childbearing potential)

          8. Have acceptable liver function:

               1. Bilirubin less than or equal to 1.5x upper limit of normal (ULN) (unless
                  attributed to Gilbert's syndrome)

               2. Aspartate aminotransferase (AST/SGOT), alanine aminotransferase (ALT/SGPT) and
                  alkaline phosphatase less than or equal to 2.5x upper limit of normal (ULN) *If
                  liver metastases are present, then less than 3x ULN is allowed.

          9. Have acceptable renal function:

             a. Calculated creatinine clearance greater than or equal to 30 mL/min

         10. Have acceptable hematologic status:

               1. Granulocyte greater than or equal to 1500 cells/mm3

               2. Platelet count greater than or equal to 100,000 (plt/mm3)

               3. Hemoglobin greater than or equal to 8 g/dl

         11. Have acceptable coagulation status:

               1. Prothrombin time (PT) within 1.5x normal limits

               2. Activated partial thromboplastin time (aPTT) within 1.5x normal limits

         12. Be nonfertile or agree to use an adequate method of contraception. Sexually active
             patients and their partners must use an effective method of contraception (hormonal or
             barrier method of birth control; or abstinence) prior to study entry and for the
             duration of study participation including for at least 3 months (males) and 6 months
             (females) after the last dose of study drug. Should a woman become pregnant or suspect
             she is pregnant while participating in this study, she should inform her treating
             physician immediately.

         13. Have read and signed the Institutional Review Board (IRB)-approved informed consent
             form (ICF) prior to any study related procedure. (In the event that the patient is
             re-screened for study participation or a protocol amendment alters the care of an
             ongoing patient, a new ICF must be signed.)

        Exclusion Criteria:

          1. History of congestive heart failure (CHF), cardiac disease, myocardial infarction
             within the past 6 months prior to Cycle 1 Day 1, left ventricular ejection fraction
             (LVEF) less than 45% by echocardiogram (ECHO), unstable arrhythmia, or evidence of
             ischemia on electrocardiogram (ECG) within 14 days prior to Cycle 1 Day 1

          2. Have a corrected QT interval (using Fridericia's correction formula) (QTcF) of >450
             msec in men and >470 msec in women

          3. Have a seizure disorder requiring anticonvulsant therapy

          4. Presence of symptomatic central nervous system metastatic disease or disease that
             requires local therapy such as radiotherapy, surgery, or increasing dose of steroids
             within the prior 2 weeks

          5. Have severe chronic obstructive pulmonary disease with hypoxemia (defined as resting
             02 saturation of less than or equal to 90% breathing room air)

          6. Have undergone major surgery within 2 weeks prior to Cycle 1 Day 1

          7. Have active, uncontrolled bacterial, viral, or fungal infections, requiring systemic
             therapy

          8. Are pregnant or nursing

          9. Received treatment with radiation therapy, surgery, chemotherapy, or investigational
             therapy within 28 days or 5 half-lives, whichever occurs first, prior to study entry
             (6 weeks for nitrosoureas or Mitomycin C)

         10. Are unwilling or unable to comply with procedures required in this protocol

         11. Have known infection with human immunodeficiency virus (HIV), hepatitis B, or
             hepatitis C. Patients with history of chronic hepatitis that is currently not active
             are eligible.

         12. Have a serious nonmalignant disease (e.g., hydronephrosis, liver failure, or other
             conditions) that could compromise protocol objectives in the opinion of the
             investigator and/or the sponsor

         13. Are currently receiving any other investigational agent

         14. Have exhibited allergic reactions to a similar structural compound, biological agent,
             or formulation

         15. Have malabsorption conditions (eg, Crohn's disease, etc) or Have undergone significant
             surgery to the gastrointestinal tract that could impair absorption or that could
             result in short bowel syndrome with diarrhea due to malabsorption
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Incidence of dose-limiting toxicities (DLTs) and treatment emergent adverse events
Time Frame:21 days
Safety Issue:
Description:A DLT is defined as a drug-related toxicity that is observed to occur within the first 28 days of treatment

Secondary Outcome Measures

Measure:Recommended Phase 2 Dose of TP-1287
Time Frame:23 months
Safety Issue:
Description:To establish the Recommended Phase 2 Dose (RP2D) for future studies with TP-1287, MTD data to be reviewed
Measure:Determine antitumor activity of TP-1287
Time Frame:20 months
Safety Issue:
Description:Objective radiographic assessment to be performed to determine antitumor activity by modified RECIST criteria

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Tolero Pharmaceuticals, Inc.

Trial Keywords

  • Tolero
  • Phase 1
  • First in human
  • Advanced Malignancy
  • Cancer
  • Metastatic
  • Progressive

Last Updated

May 21, 2019