Clinical Trials /

Phase 1, 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, dose-expansion, 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 1, First-in-human Study of Oral TP-1287 in Patients With Advanced Solid Tumors
  • Official Title: A Phase 1, 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
  • Sarcoma

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, dose-expansion, 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:

        -  During Dose Escalation: 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.

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

        -  During Dose Expansion: To evaluate the preliminary antitumor activity of TP-1287 in
           terms of objective response rate (ORR) when administered at the RP2D in patients with
           sarcoma

      Secondary Objectives:

        -  During Dose Escalation: To establish the pharmacokinetics of orally administered TP-1287

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

        -  During Dose Escalation: To study the pharmacodynamics of TP-1287 therapy

        -  During Dose Expansion: To determine the median progression-free survival (PFS) rate in
           patients with sarcoma

        -  During Dose Expansion: To evaluate the safety of TP-1287 when administered at the RP2D
           in patients with sarcoma
    

Trial Arms

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

Eligibility Criteria

        Inclusion Criteria:

          1. For Dose Escalation:

               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.

          2. For Dose Expansion:

               1. Patients who have a histologically confirmed locally advanced or metastatic
                  unresectable sarcoma

               2. Have received at least one prior line of treatment (but no more than 3 prior
                  lines) including an anthracycline.

          3. Have one or more measurable 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 at the time of informed
             consent/assent.

          6. Be greater than or equal to 18 years of age for dose escalation and expansion;
             Patients aged 16 and 17 may also participate in dose expansion if they weigh ≥40 kg

          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 or equal to 5x ULN is allowed.

                    -  If bone metastases are present, but bilirubin, AST, ALT are ≤2.5x ULN, then
                       there is no upper limit for alkaline phosphatase level. Radiographic proof
                       of bone involvement is required, and alkaline phosphatase fractionation is
                       strongly recommended to confirm the elevation is due to bony metastases.

          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.) Assent is also required for patients who
             have not attained the legal age of consent for treatments or procedures involved in
             research.

        Exclusion Criteria:

          1. History of congestive heart failure (CHF), greater than New York Heart Association
             (NYHA) Class III, myocardial infarction within the past 6 months prior to Cycle 1 Day
             1, left ventricular ejection fraction (LVEF) less than 45% by echocardiogram (ECHO) or
             multigated acquisition scan (MUGA), uncontrolled 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. Patients with previously treated and/or controlled
             metastasis are eligible.

          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, including known, active COVID-19

          8. Are pregnant or nursing

          9. Received treatment with 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) and 2 weeks for radiation therapy.

         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 symptomatic 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:During Dose Escalation: 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:During Dose Escalation: 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:During Dose Escalation: 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
Measure:During Dose Expansion: Determine the median progression-free survival (PFS) rate in patients with sarcoma
Time Frame:24 weeks
Safety Issue:
Description:Survival rate without progression

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Sumitomo Dainippon Pharma Oncology, Inc

Trial Keywords

  • Sumitomo Dainippon Pharma Oncology SDPO
  • Phase 1
  • First in human
  • Advanced Malignancy
  • Cancer
  • Metastatic
  • Sarcoma

Last Updated

May 3, 2021