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A Safety and Efficacy Study of TAK-981 Plus Pembrolizumab in Participants With Select Advanced or Metastatic 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.
 
ClinicalTrials.gov Identifier: NCT04381650
Recruitment Status : Not yet recruiting
First Posted : May 11, 2020
Last Update Posted : June 9, 2020
Sponsor:
Collaborator:
Takeda Development Center Americas, Inc.
Information provided by (Responsible Party):
Takeda

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Advanced or Metastatic Solid Tumors Drug: TAK-981 Drug: Pembrolizumab Phase 1 Phase 2

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 101 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Intervention Model Description: This study has 2 Phases. Phase 1 is dose escalation phase with sequential drug assignment. Phase 2 is parallel assignment.
Masking: None (Open Label)
Primary Purpose: Treatment
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
Estimated Study Start Date : June 30, 2020
Estimated Primary Completion Date : October 15, 2022
Estimated Study Completion Date : October 15, 2022

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Dose Escalation: TAK-981 + Pembrolizumab (fixed dose)
Escalating 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).
Drug: TAK-981
TAK-981 IV infusion.

Drug: Pembrolizumab
Pembrolizumab IV infusion.

Experimental: Dose Expansion Phase: Non-squamous NSCLC
TAK-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.
Drug: TAK-981
TAK-981 IV infusion.

Drug: Pembrolizumab
Pembrolizumab IV infusion.

Experimental: Dose Expansion Phase: Cervical Cancer
TAK-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.
Drug: TAK-981
TAK-981 IV infusion.

Drug: Pembrolizumab
Pembrolizumab IV infusion.

Experimental: Dose Expansion Phase: MSS-CRC
TAK-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.
Drug: TAK-981
TAK-981 IV infusion.

Drug: Pembrolizumab
Pembrolizumab IV infusion.




Primary Outcome Measures :
  1. Phase 1: Percentage of Participants With One or More Treatment Emergent Adverse Events (TEAEs) [ Time Frame: Up to 48 months ]
    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.

  2. Phase 1: Number of Participants With Dose Limiting Toxicities (DLTs) [ Time Frame: Up to Cycle 1 (each cycle is of 21 days) ]
    DLTs are defined using National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), v5.0 as: Any Grade 5 AE, Grade 4 hematologic AE, platelet count <10.0 x10^9/L, febrile neutropenia [>=Grade 3 neutropenia (absolute neutrophil count <1.0 ×10^9/L) with fever and/or infection], Grade 3 thrombocytopenia lasting longer than 14 days or accompanied by Grade 2 bleeding or requiring transfusion, Grade 3 immune-related adverse event such as pericarditis, pneumonitis, cardiotoxicity, hepatitis or neurotoxicity, >=Grade 3 nonhematologic toxicity, Grade 2 nonhematologic toxicities related to study drug and dose-limiting, delay in the initiation of Cycle 2 by more than 14 days due to a lack of adequate recovery of treatment-related hematological or nonhematological toxicities or missed >=1 planned dose of TAK-981 or planned dose of pembrolizumab in Cycle 1 due to treatment-related AEs.

  3. Phase 1: Number of Participants With Grade 3 or Higher Treatment Emergent Adverse Events (TEAEs) [ Time Frame: Up to 48 months ]
    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. AEs will be graded using NCI CTCAE 5.0.

  4. Phase 1: Number of Participants With One or More Serious Adverse Events (SAEs) [ Time Frame: Up to 48 months ]
    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. An SAE is any untoward medical occurrence that results in death; is life-threatening; requires inpatient hospitalization or prolongation of present hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect or is a medically important event that may not be immediately life-threatening or result in death or hospitalization, but may jeopardize the participant or may require intervention to prevent one of other outcomes listed in definition above, or involves suspected transmission via a medicinal product of an infectious agent.

  5. Phase 1: Number of Participants with One or More TEAEs Leading to Dose Modifications and Treatment Discontinuation [ Time Frame: Up to 48 months ]
    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.

  6. Phase 1: Number of Participants With Clinically Significant Laboratory Values [ Time Frame: Up to 48 months ]
    Laboratory parameters includes parameters of clinical chemistry, hematology, and urinalysis.

  7. Phase 2: Overall Response Rate (ORR) as Assessed by the Investigator According to RECIST, Version 1.1 [ Time Frame: Up to 48 months ]
    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 Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. 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.


Secondary Outcome Measures :
  1. 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. ]
  2. 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. ]
  3. 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. ]
  4. 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. ]
  5. 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. ]
  6. 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. ]
  7. 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. ]
  8. Phase 2: ORR as Defined by the Investigator According to iRECIST Modification [ Time Frame: Up to 48 months ]
    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.

  9. Phase 2: Duration of Response (DOR) [ Time Frame: Up to 48 months ]
    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.

  10. Phase 2: Progression-free Survival (PFS) [ Time Frame: Up to 48 months ]
    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.

  11. Phase 2: Time to Response (TTR) [ Time Frame: Up to 48 months ]
    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.

  12. Percentage of Participants at Each Dose Level Demonstrating Adduct Formation in Blood [ Time Frame: Up to 48 months ]
    TAK-981-SUMO adduct formation in blood will be evaluated.

  13. Percent Change in Small Ubiquitin-like Modifier (SUMO) 2/3 Signal With Pre and Post-dose in Blood [ Time Frame: Up to 48 months ]
    SUMO pathway inhibition in blood will be evaluated.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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

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 ClinicalTrials.gov identifier (NCT number): NCT04381650


Contacts
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Contact: Takeda Study Registration Call Center +1-866-835-2233 GlobalOncologyMedinfo@takeda.com

Sponsors and Collaborators
Takeda
Takeda Development Center Americas, Inc.
Investigators
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Study Director: Medical Director Clinical Science Takeda
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Responsible Party: Takeda
ClinicalTrials.gov Identifier: NCT04381650    
Other Study ID Numbers: TAK-981-1502
First Posted: May 11, 2020    Key Record Dates
Last Update Posted: June 9, 2020
Last Verified: June 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Takeda makes patient-level, de-identified data sets and associated documents available for all interventional studies after applicable marketing approvals and commercial availability have been received (or program is completely terminated), an opportunity for the primary publication of the research and final report development has been allowed, and other criteria have been met as set forth in Takeda's Data Sharing Policy (see www.TakedaClinicalTrials.com for details). To obtain access, researchers must submit a legitimate academic research proposal for adjudication by an independent review panel, who will review the scientific merit of the research and the requestor's qualifications and conflict of interest that can result in potential bias. Once approved, qualified researchers who sign a data sharing agreement are provided access to these data in a secure research environment.

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Keywords provided by Takeda:
Drug therapy
Additional relevant MeSH terms:
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Neoplasms
Pembrolizumab
Antineoplastic Agents, Immunological
Antineoplastic Agents