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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT03604783
Recruitment Status : Not yet recruiting
First Posted : July 27, 2018
Last Update Posted : October 16, 2018
Information provided by (Responsible Party):
Tolero Pharmaceuticals, Inc.

Brief Summary:
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 administered twice daily for 14 days in patients with advanced solid tumors.

Condition or disease Intervention/treatment Phase
Advanced Solid Tumors Drug: TP-1287 Phase 1

Detailed Description:

Primary Objective:

• To determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of oral TP-1287 administered twice daily for 14 days, over a range of doses in patients with advanced solid tumors.

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

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 60 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase I, First-in-human, Open-label, Dose Escalation, Safety, Pharmacokinetic, and Pharmacodynamic Study of Oral TP-1287 Administered Twice Daily for 14 Days to Patients With Advanced Solid Tumors
Estimated Study Start Date : October 2018
Estimated Primary Completion Date : February 2021
Estimated Study Completion Date : May 2021

Arm Intervention/treatment
Experimental: Single Arm TP-1287
Twice Daily dose of TP-1287 by oral administration
Drug: TP-1287
Oral twice daily dose

Primary Outcome Measures :
  1. Incidence of dose-limiting toxicities (DLTs) and treatment emergent adverse events [ Time Frame: 21 days ]

    A DLT is defined as any one of the following events observed within Cycle 1 regardless of investigator attribution unless there is a clear alternative explanation:

    • Grade 3 or greater febrile neutropenia
    • Grade 4 neutropenia for greater than or equal to 7 consecutive days
    • Grade 4 thrombocytopenia or Grade 3 thrombocytopenia with clinically significant bleeding or that requires a platelet transfusion
    • Grade 3 or 4 nonhematologic AEs including nausea, vomiting, diarrhea, and electrolyte imbalances persisting for more than 48 hours despite optimal medical management
    • Dosing delays greater than 1 week due to treatment emergent adverse events or related severe laboratory test values

  2. Determine maximum tolerated dose (MTD) [ Time Frame: 20 months ]
    If a patient experiences a DLT, up to three additional patients will be treated at that dose level. If no additional DLTs are observed in the expanded six-patient cohort, the dose will be escalated in a new cohort of three patients. If two or more patients at a given dose level experience a DLT during the first cycle, then the MTD will have been exceeded and up to a total of six patients will be treated at the next lower dose level. If O or 1 of 6 patients experiences a DLT at this previous lower dose level, this dose will be declared the MTD.

Secondary Outcome Measures :
  1. Recommended Phase 2 Dose of TP-1287 [ Time Frame: 23 months ]
    To establish the Recommended Phase 2 Dose (RP2D) for future studies with TP-1287, MTD data to be reviewed

  2. Determine antitumor activity of TP-1287 [ Time Frame: 20 months ]
    Objective radiographic assessment to be performed to determine antitumor activity by modified RECIST criteria

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  1. Have a histologically confirmed diagnosis of advanced metastatic or progressive solid tumor
  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 2
  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 or equal to 5x 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 9 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) <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, other than diagnostic 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 undergone significant surgery to the gastrointestinal tract that could impair absorption or that could result in short bowel syndrome with diarrhea due to malabsorption

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT03604783

Contact: Nissa Ashenbramer, BBA 210-931-2533
Contact: Susan Smith, MSN 210-414-7702

United States, Wisconsin
Medical College of Wisconsin Not yet recruiting
Milwaukee, Wisconsin, United States, 53226
Contact: Katy C Schroeder, BSN, RN, OCN    414-805-8843      
Principal Investigator: Ben George, MD         
Sponsors and Collaborators
Tolero Pharmaceuticals, Inc.
Study Director: Stephen Anthony, DO Tolero Pharmaceuticals

Responsible Party: Tolero Pharmaceuticals, Inc. Identifier: NCT03604783     History of Changes
Other Study ID Numbers: TP-1287-101
First Posted: July 27, 2018    Key Record Dates
Last Update Posted: October 16, 2018
Last Verified: October 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Tolero Pharmaceuticals, Inc.:
Tolero, Phase 1, First in Human, Advanced Malignancy, Cancer