Clinical Trials /

A Study to Evaluate the Safety, Tolerability and Pharmacokinetics (PK) of TAK-981 in Adult Participants With Metastatic Solid Tumors or Lymphomas

NCT03648372

Description:

The primary objective of this study is to evaluate the safety and tolerability of TAK-981 as a single agent in participants with advanced or metastatic solid tumors or lymphomas.

Related Conditions:
  • Lymphoma
  • Malignant Solid Tumor
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: A Study to Evaluate the Safety, Tolerability and Pharmacokinetics (PK) of TAK-981 in Adult Participants With Metastatic Solid Tumors or Lymphomas
  • Official Title: An Open Label, Dose-Escalation Phase I Study to Evaluate the Safety, Tolerability and Pharmacokinetics of TAK-981 in Adult Patients With Metastatic Solid Tumors or Lymphomas

Clinical Trial IDs

  • ORG STUDY ID: TAK-981-1002
  • SECONDARY ID: U1111-1214-4537
  • NCT ID: NCT03648372

Conditions

  • Neoplasms
  • Lymphoma

Interventions

DrugSynonymsArms
TAK-981TAK-981

Purpose

The primary objective of this study is to evaluate the safety and tolerability of TAK-981 as a single agent in participants with advanced or metastatic solid tumors or lymphomas.

Detailed Description

      The drug being tested in this study is called TAK-981. TAK-981 is being tested to evaluate
      safety, tolerability, and PK in participants who have locally advanced or metastatic solid
      tumors or relapsed or refractory lymphomas for whom there is no standard therapeutic
      alternative with established clinical benefit is available. The study will include a dose
      escalation phase and a dose expansion phase.

      The study will enroll approximately 80 participants, approximately 40 to 50 participants in
      the dose escalation phase and approximately 15 participants in each of the 2 cohorts of dose
      expansion phase.

      In the dose escalation phase, dose levels will be escalated based on safety, and available PK
      and pharmacodynamic data. This study will also determine the single agent recommended phase 2
      dose (RP2D). Participants in dose expansion phase will be enrolled, once maximum tolerated
      dose (MTD) or biological effective dose (BED) is determined. One of the 2 cohorts in dose
      expansion phase will consist of participants with relapsed/refractory lymphomas, and other
      cohort will consist of participants with solid tumors with no standard therapeutic option
      available with established clinical benefit.

      This multi-center trial will be conducted in the United States and Canada. The overall time
      to participate in this study is approximately 3 years. The overall time to receive treatment
      in this study is approximately 1 year. Based on decision of sponsor, participants with
      demonstrated clinical benefit can continue treatment beyond 1 year. Participants will make
      multiple visits to the clinic, and will make a final visit 30 days after receiving their last
      dose of drug or before the start of subsequent anticancer therapy, whichever occurs first for
      a follow-up assessment.
    

Trial Arms

NameTypeDescriptionInterventions
TAK-981ExperimentalTAK-981, intravenously, administered as 60 minute-infusion, once on Days 1, 4, 8, and 11 for 2 consecutive weeks, followed by 1 week rest in a 21-day treatment cycle for up to approximately 12 months or until discontinuation from the study. If TAK-981-related cumulative toxicity is observed or clinical safety, pharmacokinetics, and pharmacodynamics are supportive, the dosing schedule may be modified to evaluate a less intensive administration of TAK-981 on Days 1 and 8 in cycles of 21 days. Dose levels will be escalated based on the safety, and available PK and pharmacodynamics data. The dose expansion phase will evaluate the safety of TAK-981 at the selected MTD/BED from dose escalation phase in two cohorts of participants with solid tumors or lymphomas.
  • TAK-981

Eligibility Criteria

        Inclusion Criteria:

          1. Adult male or female participants greater than or equal to (>=)18 years old.

          2. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.

          3. Population for dose escalation and expansion.

               -  Has histologically confirmed advanced (local regionally recurrent not amenable to
                  curative therapy) or metastatic solid tumors that have no standard therapeutic
                  option with a proven clinical benefit, are intolerant or have refused them, OR

               -  Has relapsed/refractory lymphoma not amenable to therapies with proven clinical
                  benefit or who are intolerant or who refuse them. Participants with low grade
                  lymphomas such as follicular lymphoma, small lymphocytic lymphoma,
                  lymphoplasmacytoid lymphoma, and marginal zone lymphomas, may not need to exhaust
                  all available therapy. These participants can be enrolled after failure of at
                  least 2 prior systemic therapies, provided that there is not an immediate need
                  for cytoreduction. In these cases, participants who need immediate therapy for
                  tumor bulk are not eligible for this trial.

          4. If enrolled before a dose level for which there is consistent evidence of TAK-981
             pharmacodynamic effect (DLx) will not be required to have measurable disease. But once
             that DLx is determined, participants enrolling in dose escalation and expansion
             cohorts will be required to have measurable disease per RECIST version 1.1 for
             participants with solid tumors or RECIL 2017 for participants with lymphoma.

          5. Screening and post-dose tumor biopsies are required from all participants in the
             expansion cohorts and are optional during dose escalation, however once a DLx is
             identified at which there is clear evidence of TAK-981 biological effect (that is,
             observation of peripheral lymphopenia, induction of cytokines/chemokines, type 1
             interferon (IFN) signature in blood, drug-related toxicity or antitumor effect),
             subsequent participants must agree in providing a fresh tumor biopsy during the
             screening period and a second tumor biopsy as requested in the schedule of events
             (SOE). The lesion accessible for biopsy may not be the only target lesion and should
             not be located in a previously irradiated field (unless this index lesion has
             progressive disease >=20% post radiation). Ideally, the same lesion should be biopsied
             before treatment and on treatment whenever possible.

          6. Adequate bone marrow reserve and renal and hepatic function.

          7. Recovered to Grade 1, baseline or established as sequela, from all toxic effects of
             previous therapy (except alopecia, neuropathy, or autoimmune endocrinopathies with
             stable endocrine replacement therapy).

          8. Left ventricular ejection fraction (LVEF) >=40 percent (%); as measured by
             echocardiogram or multiple gated acquisition scan (MUGA).

          9. Consented to undergo serial skin punch biopsies unless the sponsor decided that there
             are already enough biopsies for proper target engagement assessment.

         10. Suitable venous access for safe drug administration and the study-required PK and
             pharmacodynamics sampling.

         11. Women of child-bearing potential participating in this study should avoid becoming
             pregnant, and male participants should avoid impregnating a female partner.
             Nonsterilized female participants of reproductive age and male participants should use
             effective methods of contraception through defined periods during and after study
             treatment as specified below. Female participants must meet 1 of the following:

               -  Postmenopausal for at least 1 year before the screening visit, or

               -  Surgically sterile, or

               -  If they are of childbearing potential, agree to practice 1 highly effective
                  method and 1additional effective (barrier) method of contraception at the same
                  time, from the time of signing of the informed consent form (ICF) through 90 days
                  after the last dose of study drug (whichever is longer), or

               -  Agree to practice true abstinence, when this is in line with the preferred and
                  usual lifestyle of the participant. (Periodic abstinence [example, calendar,
                  ovulation, symptothermal, postovulation methods], withdrawal, spermicides only,
                  and lactational amenorrhea are not acceptable methods of contraception. Female
                  and male condoms should not be used together.)

         12. Male participants, even if surgically sterilized (that is, status postvasectomy) must
             agree to 1 of the following:

               -  Agree to practice effective barrier contraception during the entire study
                  treatment period and through 120 days after the last dose of study drug, or

               -  Agree to practice true abstinence, when this is in line with the preferred and
                  usual lifestyle of the participant. (Periodic abstinence [example, calendar,
                  ovulation, symptothermal, postovulation methods], withdrawal, spermicides only,
                  and lactational amenorrhea are not acceptable methods of contraception. Female
                  and male condoms should not be used together.)

        Exclusion Criteria:

          1. Treatment with systemic anticancer treatments or investigational products within 14
             days before the first dose of study drug or 5 half-lives, whichever is shorter.

          2. History of uncontrolled brain metastasis.

          3. Is receiving any live vaccine (example, varicella, pneumococcus) within 4 weeks of
             initiation of study treatment.

          4. Has received extended field radiotherapy less than or equal to (<=) 4 weeks before the
             start of treatment (<=2 weeks for limited field radiation for palliation), and who has
             not recovered to grade 1 or better from related side effects of such therapy (except
             for alopecia).

          5. History of any of the following <=6 months before first dose: congestive heart failure
             New York Heart Association Grade III or IV, unstable angina, myocardial infarction,
             unstable symptomatic ischemic heart disease, uncontrolled hypertension despite
             appropriate medical therapy, ongoing symptomatic cardiac arrhythmias of >Grade 2,
             pulmonary embolism, or symptomatic cerebrovascular events, or any other serious
             cardiac condition.

          6. Baseline prolongation of the corrected QT (QTc) interval (example, repeated
             demonstration of QTc interval >480 milliseconds (ms), history of congenital long QT
             syndrome, or torsades de pointes).

          7. Psychiatric illness/social circumstances that would limit compliance with study
             requirements and substantially increase the risk of adverse events (AEs) or has
             compromised ability to provide written informed consent.

          8. Admission or evidence of illicit drug use, drug abuse, or alcohol abuse.

          9. History of autoimmune disease requiring systemic immunosuppressive therapy.

         10. Active infection.

         11. Known hepatitis B virus (HBV) surface antigen seropositive or detectable hepatitis C
             infection viral load. Note: Participants who have positive hepatitis B core antibody
             or hepatitis B surface antigen antibody can be enrolled but must have an undetectable
             hepatitis B viral load.

         12. Known history of human immunodeficiency virus infection or any other relevant
             congenital or acquired immunodeficiency.

         13. Receiving or requiring the continued use of medications that are known to be strong or
             moderate inhibitors and inducers of CYP3A4/5 and strong permeability glycoprotein
             (P-gp) inhibitors. To participate in this study, such participants should discontinue
             use of such agents for at least 2 weeks before receiving a dose of TAK-981.

         14. Lymphomas with leukemic expression.

         15. Female participants who are lactating and breastfeeding or have a positive serum
             pregnancy test during the screening period or a positive urine pregnancy test on Day 1
             before first dose of study drug.

         16. Participants requires the use of drugs known to prolong QTc interval.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Number of Participants Reporting one or More Treatment Emergent Adverse Events (TEAEs)
Time Frame:Up to 36 months
Safety Issue:
Description:

Secondary Outcome Measures

Measure:Cmax: Maximum Observed Plasma Concentration for TAK-981
Time Frame:Cycle 1 Day 1 pre-dose and at multiple time points (up to 48 hours) post dose; Cycle 1 Day 8 pre-dose and at multiple time points (up to 24 hours) post dose (Cycle length is equal to [=] 21 days)
Safety Issue:
Description:
Measure:Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for TAK-981
Time Frame:Cycle 1 Day 1 pre-dose and at multiple time points (up to 48 hours) post dose; Cycle 1 Day 8 pre-dose and at multiple time points (up to 24 hours) post dose (Cycle length =21 days)
Safety Issue:
Description:
Measure:AUCt: Area Under the Plasma Concentration-time Curve from Time 0 to Time t Over the Dosing Interval for TAK-981
Time Frame:Cycle 1 Day 1 pre-dose and at multiple time points (up to 48 hours) post dose; Cycle 1 Day 8 pre-dose and at multiple time points (up to 24 hours) post dose (Cycle length =21 days)
Safety Issue:
Description:
Measure:AUC∞: Area Under the Plasma Concentration-time Curve from Time 0 to Infinity for TAK-981
Time Frame:Cycle 1 Day 1 pre-dose and at multiple time points (up to 48 hours) post dose; Cycle 1 Day 8 pre-dose and at multiple time points (up to 24 hours) post dose (Cycle length =21 days)
Safety Issue:
Description:
Measure:Terminal Disposition Phase Half-life (t1/2z) for TAK-981
Time Frame:Cycle 1 Day 1 pre-dose and at multiple time points (up to 48 hours) post dose; Cycle 1 Day 8 pre-dose and at multiple time points (up to 24 hours) post dose (Cycle length =21 days)
Safety Issue:
Description:
Measure:Total Clearance After Intravenous Administration (CL) for TAK-981
Time Frame:Cycle 1 Day 1 pre-dose and at multiple time points (up to 48 hours) post dose; Cycle 1 Day 8 pre-dose and at multiple time points (up to 24 hours) post dose (Cycle length =21 days)
Safety Issue:
Description:
Measure:Volume of Distribution at Steady State After Intravenous Administration (Vss) for TAK-981
Time Frame:Cycle 1 Day 1 pre-dose and at multiple time points (up to 48 hours) post dose; Cycle 1 Day 8 pre-dose and at multiple time points (up to 24 hours) post dose (Cycle length =21 days)
Safety Issue:
Description:
Measure:Overall Response Rate (ORR)
Time Frame:From the first dose until best response is achieved (up to approximately 3 years)
Safety Issue:
Description:ORR is defined as percentage of participants who achieve complete response (CR) and partial response (PR) through the study (approximately 3 years), as determined by the investigator according to the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST V1.1) for participants with solid tumors and Response Evaluation Criteria in Lymphoma (RECIL) for participants with lymphoma.
Measure:Duration of Response (DOR)
Time Frame:From the time of documentation of tumor response to the first recorded occurrence of disease progression (PD) or death from any cause (whichever occurs first), through end of study (up to approximately 3 years)
Safety Issue:
Description:DOR will be determined by the investigator according to RECIST V1.1 for participants with solid tumors and RECIL for participants with lymphoma.
Measure:Disease Control Rate (DCR)
Time Frame:From the first dose until best response is achieved (up to approximately 3 years)
Safety Issue:
Description:DCR is defined as percentage of participants who achieve stable disease (SD) or better greater than (>) 6 weeks during the study in response-evaluable population, as determined by the investigator according to RECIST V1.1 for participants with solid tumors and RECIL for participants with lymphoma.
Measure:Progression-free Survival (PFS)
Time Frame:From the date of the first dose administration to the date of first documentation of PD or death due to any cause whichever occurs first, through the end of the study (up to approximately 3 years)
Safety Issue:
Description:PFS will be determined by the investigator according to RECIST V1.1 for participants with solid tumors and RECIL for participants with lymphoma.
Measure:Time to Response (TTR)
Time Frame:From the date of first study drug administration to the date of first documented PR or better (up to approximately 3 years)
Safety Issue:
Description:TTR will be determined by the investigator according to RECIST V1.1 for participants with solid tumors and RECIL for participants with lymphoma.
Measure:Percentage of Participants at Each Dose Level Demonstrating Adduct Formation in Post-dose Skin or Tumor Biopsies
Time Frame:Up to Cycle 1 (approximately 3 weeks) (Cycle length =21 days)
Safety Issue:
Description:
Measure:Percent Change in Small Ubiquitin-like Modifier (SUMO) 2/3 Signal With Pre and Post-dose Skin or Tumor Biopsies at Each Dose Level
Time Frame:Up to Cycle 1 (approximately 3 weeks) (Cycle length =21 days)
Safety Issue:
Description:

Details

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

Trial Keywords

  • Drug therapy

Last Updated