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A Safety and Efficacy Study of TAK-981 Plus Pembrolizumab in Participants With Select Advanced or Metastatic Solid Tumors

NCT04381650

Description:

The purpose of this study is to determine the safety and tolerability of TAK-981 in combination with pembrolizumab in participants with select solid tumor indications and to establish the recommended phase 2 dose (RP2D) during Phase 1b of study and to evaluate the preliminary efficacy of TAK-981 at the RP2D in combination with pembrolizumab in participants with select solid tumor indications in Phase 2 of the study.

Related Conditions:
  • Cervical Adenocarcinoma
  • Cervical Adenosquamous Carcinoma
  • Cervical Squamous Cell Carcinoma
  • Colorectal Carcinoma
  • Malignant Solid Tumor
  • Non-Squamous Non-Small Cell Lung Carcinoma
Recruiting Status:

Not yet recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: A Safety and Efficacy Study of TAK-981 Plus Pembrolizumab in Participants With Select Advanced or Metastatic Solid Tumors
  • Official Title: A Phase 1b/2 Study of TAK-981 Plus Pembrolizumab to Evaluate the Safety, Tolerability, and Antitumor Activity of the Combination in Patients With Select Advanced or Metastatic Solid Tumors

Clinical Trial IDs

  • ORG STUDY ID: TAK-981-1502
  • NCT ID: NCT04381650

Conditions

  • Advanced or Metastatic Solid Tumors

Interventions

DrugSynonymsArms
TAK-981Dose Escalation: TAK-981 + Pembrolizumab (fixed dose)
PembrolizumabDose Escalation: TAK-981 + Pembrolizumab (fixed dose)

Purpose

The purpose of this study is to determine the safety and tolerability of TAK-981 in combination with pembrolizumab in participants with select solid tumor indications and to establish the recommended phase 2 dose (RP2D) during Phase 1b of study and to evaluate the preliminary efficacy of TAK-981 at the RP2D in combination with pembrolizumab in participants with select solid tumor indications in Phase 2 of the study.

Detailed Description

      The drug being tested in this study is called TAK-981. TAK-981 is being tested to treat
      people who have select advanced or metastatic solid tumors. The study will include a dose
      escalation phase and a dose expansion phase.

      The study will enroll approximately 101 patients, approximately 32 participants in the dose
      escalation phase and approximately 9 to 23 participants in each of the 3 cohorts of dose
      expansion phase. Participants will receive escalating doses of TAK-981 and fixed dose of
      pembrolizumab until RP2D is determined:

      • Dose Escalation: TAK-981 + Pembrolizumab (fixed dose)

      Once RP2D is determined, participants of select advanced or metastatic solid tumors will
      receive TAK-981 in below defined cohorts in the expansion phase:

        -  Expansion Phase: Non-squamous NSCLC

        -  Expansion Phase: Cervical Cancer

        -  Expansion Phase: Microsatellite Stable Colorectal Cancer (MSS-CRC)

      This multi-center trial will be conducted worldwide. The overall time to participate in this
      study is 48 months. Participants will make multiple visits to the clinic, and
      progression-free survival follow-up for maximum up to 12 months after last dose of study
      drug.
    

Trial Arms

NameTypeDescriptionInterventions
Dose Escalation: TAK-981 + Pembrolizumab (fixed dose)ExperimentalEscalating doses of TAK-981 with starting dose of 40 mg, intravenous (IV) infusion, on Days 1, 4, 8 and 11 in each 21-day Treatment Cycle and pembrolizumab 200 mg, IV infusion, as a fixed dose every 3 weeks in 21-day Treatment Cycle until RP2D is determined (for a maximum of 24 months).
  • TAK-981
  • Pembrolizumab
Dose Expansion Phase: Non-squamous NSCLCExperimentalTAK-981 at RP2D as IV infusion in participants with non-squamous non-small cell lung cancer (NSCLC) on Days 1, 4, 8 and 11 in each 21-day Treatment Cycle up to disease progression or 12-months and pembrolizumab 200 mg IV infusion as a fixed dose every 3 weeks in 21-day Treatment Cycle for a maximum of 24 months.
  • TAK-981
  • Pembrolizumab
Dose Expansion Phase: Cervical CancerExperimentalTAK-981 at RP2D as IV infusion in participants with cervical cancer on Days 1, 4, 8 and 11 in each 21-day Treatment Cycle up to disease progression or 12-months and pembrolizumab 200 mg IV infusion as a fixed dose every 3 weeks in 21-day Treatment Cycle for a maximum of 24 months.
  • TAK-981
  • Pembrolizumab
Dose Expansion Phase: MSS-CRCExperimentalTAK-981 at RP2D as IV infusion in participants with microsatellite stable colorectal cancer (MSS-CRC) on Days 1, 4, 8 and 11 in each 21-day Treatment Cycle up to disease progression or 12-months and pembrolizumab 200 mg IV infusion as a fixed dose every 3 weeks in 21-day Treatment Cycle for a maximum of 24 months.
  • TAK-981
  • Pembrolizumab

Eligibility Criteria

        Inclusion Criteria:

          1. Has a histologically or cytologically documented, advanced (metastatic and/or
             unresectable) cancer as listed below that is incurable and for which prior standard
             first-line treatment has failed: Note: Prior neoadjuvant or adjuvant therapy included
             in initial treatment may not be considered first- or later-line standard of care
             treatment unless such treatments were completed less than 12 months prior to the
             current tumor recurrence.

             A. Non-squamous non-small cell lung cancer (NSCLC) that has progressed to no more than
             1 prior systemic immune checkpoint inhibitor (CPI)/anti- programmed cell death protein
             1/ligand (PD-1/L1)-containing therapy. In phase 2, non-squamous NSCLC participants
             must have not shown evidence of tumor progression during the first 5 months of
             treatment with first-line CPI/anti-PD-(1/L1)-containing therapy.

             Note: Participants with known driver mutations/genomic aberrations (e.g. epidermal
             growth factor receptor [EGFR], B-Raf proto-oncogene mutation V600E [BRAF V600E], and
             ROS proto-oncogene 1 [ROS1] sensitizing mutations, neurotrophic receptor tyrosine
             kinase [NRTK] gene fusions, and anaplastic lymphoma kinase [ALK] rearrangements) must
             have also shown progressive disease after treatment with a commercially available
             targeted therapy.

             B. CPI-naive cervical cancer (squamous cell carcinoma, adenosquamous carcinoma or
             adenocarcinoma of the cervix) participants who have received no more than 1 prior
             systemic line of therapy for recurrent or Stage IVB cervical cancer. Note: The
             following cervical tumors are not eligible: minimal deviation/adenoma malignum,
             gastric-type adenocarcinoma, clear-cell carcinoma, and mesonephric carcinoma.
             Histologic confirmation of the original primary tumor is required via pathology
             report. Note: First-line treatment must have consisted of platinum-containing doublet.
             Chemotherapy administered concurrently with primary radiation (e.g., weekly cisplatin)
             is not counted as a systemic chemotherapy regimen.

             C. CPI-naïve microsatellite stable-colorectal cancer (MSS-CRC) participants who have
             progressed on no more than 3 chemotherapy regimens.

             Note: Participants must have received prior treatment with fluoropyrimidine-,
             oxaliplatin-, and irinotecan-containing regimens if indicated.

          2. Has at least 1 radiologically measurable lesion based on RECIST, Version 1.1. Tumor
             lesions situated in a previously irradiated area are considered measurable if
             progression has been demonstrated in such lesions.

          3. Has a performance status of 0 or 1 on the Eastern Cooperative Group (ECOG) Performance
             Scale.

          4. Has left ventricular ejection fraction (LVEF) ≥40%; as measured by echocardiogram
             (ECHO) or multiple-gated acquisition (MUGA) scan.

          5. Has recovered to Grade 1 or baseline from all toxicity associated with previous
             therapy or have the toxicity established as sequela. Note: Has a neuropathy ≤Grade 2,
             any grade alopecia, or autoimmune endocrinopathies with stable replacement therapy are
             permitted.

          6. Demonstrate adequate organ function as described below:

        A. Platelet count ≥75.0 × 10^9/L. B. Absolute neutrophil count (ANC) ≥1.0 × 10^9/L. C.
        Hemoglobin ≥85 g/L (red blood cell [RBC] transfusion allowed ≥14 days before assessment).

        D. Estimated creatinine clearance using the Cockcroft-Gault formula ≥45 mL/minute for
        participants with serum creatinine concentrations above the upper limit of normal (ULN).

        E. Aspartate aminotransferase (AST, GOT) and alanine aminotransferase (ALT, GPT) ≤3.0 ×
        ULN; bilirubin ≤1.5 × ULN. Participants with Gilbert's syndrome may have a bilirubin level
        >1.5 × ULN, per discussion between the investigator and the medical monitor.

        Exclusion Criteria:

          1. Has received extended field radiotherapy ≤4 weeks before the start of treatment (≤7
             days for limited field radiation for palliation outside the chest or brain).

          2. Has a history of uncontrolled brain metastasis (evidence of progression by imaging
             over a period of 4 weeks and/or neurologic symptoms that have not returned to
             baseline). Participant with treated brain metastases are allowed provided they are
             radiologically stable, without evidence of progression for at least 4 weeks by repeat
             imaging, clinically stable, and without requirement of steroid treatment for at least
             14 days prior to first dose of study treatment. Note: For asymptomatic participants,
             screening brain imaging is not required.

          3. Second malignancy within the previous 3 years, except treated basal cell or localized
             squamous skin carcinomas, localized prostate cancer, cervical carcinoma in situ,
             resected colorectal adenomatous polyps, breast cancer in situ, or other malignancy for
             which the participant is not on active anticancer therapy.

          4. Major surgery ≤14 days from the first dose of study drug and not recovered fully from
             any complications from surgery.

          5. Has a history of immune-related adverse events (AEs) related to treatment with immune
             CPIs that required treatment discontinuation.

          6. Is receiving or requires the continued use of medications that are known to be strong
             or moderate inhibitors and inducers of cytochrome P-450 (CYP) 3A4/5. To participate in
             this study, such participant should discontinue use of such agents for at least 2
             weeks (1 week for CYP3A4/5 inhibitors) before receiving a dose of TAK-981.

          7. Had received any live vaccine (e.g., varicella, pneumococcus) within 4 weeks of
             initiation of study treatment.

          8. Baseline prolongation of the QT interval corrected using Fridericia's formula (QTcF)
             (eg, repeated demonstration of QTcF interval >480 ms, history of congenital long QT
             syndrome, or torsades de pointes).

          9. Has a history of autoimmune disease requiring systemic immunosuppressive therapy with
             daily doses of prednisone >10 mg/day or equivalent doses, or any other form of
             immunosuppressive therapy. Hormone therapy (e.g., thyroxine, insulin, or physiologic
             corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not
             considered an excluded form of systemic treatment of an autoimmune disease.

         10. Has a history of noninfectious pneumonitis that required steroids or a history of
             interstitial lung disease.

         11. Has a evidence of active, non-infectious pneumonitis.

         12. Has a history of allogeneic tissue or solid organ transplant.

         13. Has a active infection requiring systemic therapy.

         14. Has a known history of HIV infection or any other relevant congenital or acquired
             immunodeficiency.

         15. Has a known hepatitis B virus 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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Phase 1: Percentage of Participants With One or More Treatment Emergent Adverse Events (TEAEs)
Time Frame:Up to 48 months
Safety Issue:
Description:An AE is any untoward medical occurrence in a participant administered a medicinal investigational drug. The untoward medical occurrence does not necessarily have to have a causal relationship with treatment. A TEAE is defined as an AE that occurs after administration of first dose of study drug and through 30 days after last dose of study drug or until start of subsequent antineoplastic therapy.

Secondary Outcome Measures

Measure:Phase 2: Cmax: Maximum Observed Plasma Concentration for TAK-981
Time Frame:Cycle 1 (each cycle is 21 days) Days 1, 4, 8 and 11, pre-dose and at multiple timepoints (Up to 24 hours) post-dose; Cycle 2, Days 1 and 8, at multiple time points post-dose.
Safety Issue:
Description:
Measure:Phase 2: Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for TAK-981
Time Frame:Cycle 1 (each cycle is 21 days) Days 1, 4, 8 and 11, pre-dose and at multiple timepoints (Up to 24 hours) post-dose; Cycle 2, Days 1 and 8, at multiple time points post-dose.
Safety Issue:
Description:
Measure:Phase 2: 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 (each cycle is 21 days) Days 1, 4, 8 and 11, pre-dose and at multiple timepoints (Up to 24 hours) post-dose; Cycle 2, Days 1 and 8, at multiple time points post-dose.
Safety Issue:
Description:
Measure:Phase 2: AUC∞: Area Under the Plasma Concentration-time Curve from Time 0 to Infinity for TAK-981
Time Frame:Cycle 1 (each cycle is 21 days) Days 1, 4, 8 and 11, pre-dose and at multiple timepoints (Up to 24 hours) post-dose; Cycle 2, Days 1 and 8, at multiple time points post-dose.
Safety Issue:
Description:
Measure:Phase 2: t1/2z: Terminal Disposition Phase Half-life for TAK-981
Time Frame:Cycle 1 (each cycle is 21 days) Days 1, 4, 8 and 11, pre-dose and at multiple timepoints (Up to 24 hours) post-dose; Cycle 2, Days 1 and 8, at multiple time points post-dose.
Safety Issue:
Description:
Measure:Phase 2: CL: Total Clearance After Intravenous Administration for TAK-981
Time Frame:Cycle 1 (each cycle is 21 days) Days 1, 4, 8 and 11, pre-dose and at multiple timepoints (Up to 24 hours) post-dose; Cycle 2, Days 1 and 8, at multiple time points post-dose.
Safety Issue:
Description:
Measure:Phase 2: Vss: Volume of Distribution at Steady State After Intravenous Administration for TAK-981
Time Frame:Cycle 1 (each cycle is 21 days) Days 1, 4, 8 and 11, pre-dose and at multiple timepoints (Up to 24 hours) post-dose; Cycle 2, Days 1 and 8, at multiple time points post-dose.
Safety Issue:
Description:
Measure:Phase 2: ORR as Defined by the Investigator According to iRECIST Modification
Time Frame:Up to 48 months
Safety Issue:
Description:ORR is defined as the percentage of participants who achieve Complete Response (CR) and Partial Response (PR)(determined by the investigator) during the study according to consensus guideline developed by the RECIST Working Group for the use of modified RECIST, Version 1.1 in cancer immunotherapy trials (iRECIST). CR is defined as disappearance of all target lesions; PR is defined as at least 30% decrease in sum of diameters (SoD) of target lesions.
Measure:Phase 2: Duration of Response (DOR)
Time Frame:Up to 48 months
Safety Issue:
Description:DOR is defined as a time from the time of first 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 48 months). PD is defined as at least a 20% increase in the sum of the longest diameter (LD) of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions.
Measure:Phase 2: Progression-free Survival (PFS)
Time Frame:Up to 48 months
Safety Issue:
Description:PFS is defined as time 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 48 months). PD is defined as at least a 20% increase in the sum of the longest diameter (LD) of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions.
Measure:Phase 2: Time to Response (TTR)
Time Frame:Up to 48 months
Safety Issue:
Description:TTR is defined as time from the date of first study drug administration to the date of first documented PR or better (up to approximately 48 months). PR is defined as at least 30% decrease in sum of diameters (SoD) of target lesions.
Measure:Percentage of Participants at Each Dose Level Demonstrating Adduct Formation in Blood
Time Frame:Up to 48 months
Safety Issue:
Description:TAK-981-SUMO adduct formation in blood will be evaluated.
Measure:Percent Change in Small Ubiquitin-like Modifier (SUMO) 2/3 Signal With Pre and Post-dose in Blood
Time Frame:Up to 48 months
Safety Issue:
Description:SUMO pathway inhibition in blood will be evaluated.

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Takeda

Trial Keywords

  • Drug therapy

Last Updated

May 6, 2020