A Study of TAK-981 Given With Pembrolizumab in Participants With Select Advanced or Metastatic Solid Tumors

JRCT ID: jRCT2031210417

Registered date:09/11/2021

Basic Information

• Recruitment status: Recruiting
• Health condition(s) or Problem(s) studied: Advanced or Metastatic Solid Tumors
• Date of first enrollment: 17/08/2020
• Target sample size: 231
• Countries of recruitment: United States,Japan
• Study type: Interventional

Intervention(s)

Dose Escalation: TAK-981 + Pembrolizumab (Fixed Dose)
Escalating doses of TAK-981 with starting dose of 40 mg (For Japan-specific Lead-in, the dose confirmed to be tolerable in TAK-981-1501 study), intravenous (IV) infusion, on Days 1, 4, 8 and 11 or Days 1 and 8 or Days 1, 8 and 15 in each 21-day Treatment Cycle and pembrolizumab 200 mg, IV infusion, as a fixed dose every 3 weeks on Day 1 of 21-day Treatment Cycle until recommended Phase 2 dose (RP2D) is determined (for a maximum of 24 months).

Dose Expansion Phase: Cohort A: Non-squamous NSCLC
TAK-981 as IV infusion in participants with non-squamous NSCLC on Days 1, 4, 8 and 11 or Days 1 and 8 or Days 1, 8 and 15 in each 21-day Treatment Cycle up to disease progression or 24-months and pembrolizumab 200 mg IV infusion as a fixed dose every 3 weeks on Day 1 of 21-day Treatment Cycle for a maximum of 24 months.

Dose Expansion Phase: Cohort B: Cervical Cancer
TAK-981 as IV infusion in participants with cervical cancer on Days 1, 4, 8 and 11 or Days 1 and 8 or Days 1, 8 and 15 in each 21-day Treatment Cycle up to disease progression or 24-months and pembrolizumab 200 mg IV infusion as a fixed dose every 3 weeks on Day 1 of 21-day Treatment Cycle for a maximum of 24 months.

Dose Expansion Phase: Cohort C: MSS-CRC
TAK-981 as IV infusion in participants with MSS-CRC on Days 1, 4, 8 and 11 or Days 1 and 8 or Days 1, 8 and 15 in each 21-day Treatment Cycle up to disease progression or 24-months and pembrolizumab 200 mg IV infusion as a fixed dose every 3 weeks on Day 1 of 21-day Treatment Cycle for a maximum of 24 months.

Dose Expansion Phase: Cohort D: Cutaneous Melanoma
TAK-981 as IV infusion in participants with cutaneous melanoma on Days 1, 4, 8 and 11 or Days 1 and 8 or Days 1, 8 and 15 in each 21-day Treatment Cycle up to disease progression or 24-months and pembrolizumab 200 mg IV infusion as a fixed dose every 3 weeks on Day 1 of 21-day Treatment Cycle for a maximum of 24 months.

Dose Expansion Phase: Cohort E: Squamous NSCLC
TAK-981 as IV infusion in participants with squamous NSCLC on Days 1, 4, 8 and 11 or Days 1 and 8 or Days 1, 8 and 15 in each 21-day Treatment Cycle up to disease progression or 24-months and pembrolizumab 200 mg IV infusion as a fixed dose every 3 weeks on Day 1 of 21-day Treatment Cycle for a maximum of 24 months.

Dose Expansion Phase: Cohort F: CPI Refractory Squamous or Nonsquamous NSCLC
TAK-981 as IV infusion in participants with checkpoint inhibitors (CPI) refractory squamous or nonsquamous NSCLC on Days 1, 4, 8 and 11 or Days 1 and 8 or Days 1, 8 and 15 in each 21-day Treatment Cycle up to disease progression or 24-months and pembrolizumab 200 mg IV infusion as a fixed dose every 3 weeks on Day 1 of 21-day Treatment Cycle for a maximum of 24 months.

Outcome(s)

Primary Outcome

1.Phase 1: Number 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. AEs will be evaluated according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), Version 5.0 except cytokine release syndrome (CRS), will be graded according to American society for transplantation and cellular therapy (ASCST) Consensus Grading for CRS.

2.Phase 1: Number of Participants With Dose Limiting Toxicities (DLTs)
Time Frame: Up to Cycle 1 (each cycle is of 21 days)
DLTs will be evaluated according toNCI CTCAE, Version 5.0 except CRS, will be graded according to ASCST Consensus Grading for CRS.

3.Phase 1: Number of Participants With Grade 3 or Higher Treatment Emergent Adverse Events (TEAEs)
Time Frame: Up to 48 months

4.Phase 1: Number of Participants With One or More Serious Adverse Events (SAEs)
Time Frame: Up to 48 months
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

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 60 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 RECIST Version 1.1.

Secondary Outcome

1.Phase 1: Cmax: Maximum Observed Plasma Concentration for TAK-981
Time Frame: Cycle 1 (each cycle is 21 days) Days 1 and 8 pre-dose and at multiple timepoints (Up to 24 hours); Days 4 and 11: at the end of infusion; Cycle 2, Days 1 and 8, at the end of infusion and at 2 hours post-dose

2.Phase 1: Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for TAK-981
Time Frame: Cycle 1 (each cycle is 21 days) Days 1 and 8 pre-dose and at multiple timepoints (Up to 24 hours); Days 4 and 11: at the end of infusion; Cycle 2, Days 1 and 8, at the end of infusion and at 2 hours post-dose

3.Phase 1: 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 and 8 pre-dose and at multiple timepoints (Up to 24 hours); Days 4 and 11: at the end of infusion; Cycle 2, Days 1 and 8, at multiple time points the end of infusion and at 2 hours post-dose

4.Phase 1: AUCinf: 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 and 8 pre-dose and at multiple timepoints (Up to 24 hours); Days 4 and 11: at the end of infusion; Cycle 2, Days 1 and 8, at the end of infusion and at 2 hours post-dose

5.Phase 1: t1/2z: Terminal Disposition Phase Half-life for TAK-981
Time Frame: Cycle 1 (each cycle is 21 days) Days 1 and 8 pre-dose and at multiple timepoints (Up to 24 hours); Days 4 and 11: at the end of infusion; Cycle 2, Days 1 and 8, at the end of infusion and at 2 hours post-dose

6.Phase 1: CL: Total Clearance After Intravenous Administration for TAK-981
Time Frame: Cycle 1 (each cycle is 21 days) Days 1 and 8 pre-dose and at multiple timepoints (Up to 24 hours); Days 4 and 11: at the end of infusion; Cycle 2, Days 1 and 8, at the end of infusion and at 2 hours post-dose

7.Phase 1: Vss: Volume of Distribution at Steady State After Intravenous Administration for TAK-981
Time Frame: Cycle 1 (each cycle is 21 days) Days 1 and 8 pre-dose and at multiple timepoints (Up to 24 hours); Days 4 and 11: at the end of infusion; Cycle 2, Days 1 and 8, at the end of infusion and at 2 hours post-dose

8.Phases 1 and 2: ORR as Defined by the Investigator According to consensus guideline developed by the RECIST Working Group for the use of modified RECIST, Version 1.1 in cancer immunotherapy trials (iRECIST) Modification
Time Frame: Up to 60 months

9.Phases 1 and 2: Disease Control Rate (DCR)
Time Frame: Up to 60 months
DCR is defined as the percentage of participants who achieve stable disease (SD) or better (CR+PR+SD determined by the investigator) during the study.

10.Phases 1 and 2: Durable Response Rate (DRR)
Time Frame: Up to 60 months
DRR is defined as the rate of objective responses (CR + PR) maintained for at least 6 months initiating at any time within 12 months of commencing therapy.

11.Phases 1 and 2: Duration of Response (DOR)
Time Frame: Up to 60 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 60 months).

12.Phases 1 and 2: Progression-free Survival (PFS)
Time Frame: Up to 60 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).

13.Phases 1 and 2: Time to Response (TTR)
Time Frame: Up to 60 months
TTR is defined as time from the date of the first dose to the date of first documentation of objective tumor response (CR and PR as determined by the investigator). (up to approximately 48 months).

14.Phases 1 and 2: Time to Progression (TTP)
Time Frame: Up to 60 months
TTP is defined as the from the date of the first dose administration to the date of the first documentation of PD as defined by standard disease criteria.

15.Phase 2: Overall Survival (OS)
Time Frame: Up to 60 months
OS is defined as the time from the date of the first dose administration to the date of death. Participants without documentation of death at the time of analysis will be censored at the date last known to be alive.

16.Phase 1: Percentage of Participants at Each Dose Level Demonstrating Adduct Formation in Blood
Time Frame: Up to 48 months
TAK-981- Small Ubiquitin-like Modifier (SUMO) adduct formation in blood will be evaluated.

17.Phase 1: Percent Change in 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.

18.Phase 2: Percentage of Participants With One or More TEAEs
Time Frame: Up to 60 months

19.Phase 2: Number of Participants With Grade 3 or Higher TEAEs
Time Frame: Up to 60 months

20.Phase 2: Number of Participants with One or More TEAEs Leading to Dose Modifications and Treatment Discontinuation
Time Frame: Up to 60 months

Key inclusion & exclusion criteria

• Age minimum: >= 18age old
• Age maximum: Not applicable
• Gender: Both

Include criteria

1) Has a histologically or cytologically documented, advanced (metastatic and/or unresectable) cancer as listed below that is incurable: 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) for which prior standard first-line treatment containing an anti-programmed cell death protein 1/programmed cell death protein 1 ligand (PD-1/PD-L1) checkpoint inhibitor (CPI) alone or in combination has failed and that has progressed on no more than 1 prior systemic therapy. For the Phase1b Japan-specific Lead-in, non-squamous NSCLC that has progressed to no more than 1 prior systemic immune CPI/anti-PD-(1/L1)-containing therapy. In Phase 2, participants with nonsquamous NSCLC must have not received more than 1 prior systemic therapy and must not have presented with disease progression during the first 6 months of treatment with first-line CPI/anti-PD-(1/L1)-containing therapy.
Note: In Phase 1, participants with nonsquamous NSCLC and 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. In Phase 2, participants with driver mutations are not eligible.

B. CPI-naive cervical cancer (squamous cell carcinoma, adenosquamous carcinoma or adenocarcinoma of the cervix) participants for whom prior standard first-line treatment has failed and who have received no more than 1 prior systemic line of therapy for recurrent or Stage IVB cervical cancer. For the Phase1b Japan-specific Lead-in, CPI-naive cervical cancer (squamous cell carcinoma, adenosquamous carcinoma or adenocarcinoma of the cervix) patients for whom prior standard first-line treatment for recurrent or Stage IVB cervical cancer has failed.
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-naive microsatellite stable-colorectal cancer (MSS-CRC) participants for whom prior standard first-line treatment has failed and 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.
For the Phase1b Japan-specific Lead-in, MSS-CRC patients who have no standard therapeutic option with a proven clinical benefit, are intolerant, or have refused them.
D. Unresectable Stage III or Stage IV cutaneous melanoma that has not received prior therapy in the metastatic setting.
Note: Participants with acral melanoma are not eligible. Participants who have presented with disease relapse after >=6 months of the last dose of CPI or BRAF-mitogen-activated protein kinase kinase (MEK) inhibitor in the adjuvant setting are eligible.

E. Squamous NSCLC for which prior standard first-line treatment containing an anti-PD-(1/L1) checkpoint inhibitor alone or in combination has failed. Participant must have not received more than 1 prior systemic therapy and must not have presented with disease progression during the first 6 months of treatment with first-line CPI/anti-PD-(1/L1)-containing therapy.

F. Squamous or nonsquamous NSCLC for which prior standard first-line treatment containing an anti-PD-(1/L1) checkpoint inhibitor alone or in combination has failed within 6 months from the initiation of the CPI. Participants must not have received more than 1 prior systemic therapy in the metastatic setting.
Note: Participants with driver mutations are not eligible.

2) Has at least 1 radiologically measurable lesion based on Response Evaluation Criteria in Solid Tumors (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 Oncology (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 x 10^9/L.
B. Absolute neutrophil count (ANC) >=1.0 x 10^9/L.
C. Hemoglobin >=85 g/L (red blood cell [RBC] transfusion allowed >=14 days before assessment).
D. Calculated creatinine clearance >=30 mL/min using the Cockcroft-Gault formula.
E. Aspartate aminotransferase (AST, GOT) and alanine aminotransferase (ALT, GPT) =<3.0 times the upper limit of normal (ULN), <5.0 times the ULN if liver enzyme elevations are due to liver metastases; bilirubin =<1.5 times the ULN. Participants with Gilbert's syndrome may have a bilirubin level >1.5 times the ULN, per discussion between the investigator and the medical monitor.

Exclude criteria

1) 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.
2) 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.
3) Major surgery =<14 days from the first dose of study drug and not recovered fully from any complications from surgery.
4) History of immune-related adverse events (AEs) related to treatment with immune CPIs that required treatment discontinuation.
5) 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 and strong P-glycoprotein (Pgp) inhibitors.
6) Baseline prolongation of the QT interval corrected using Fridericia's formula (QTcF) (e.g, repeated demonstration of QTcF interval >480 milliseconds (ms), history of congenital long QT syndrome, or torsades de pointes).
7) 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 thyroid, adrenal or pituitary insufficiency) for endocrinopathies are not considered prohibited forms of systemic treatment of an autoimmune disease.
8) Has a history of noninfectious pneumonitis that required steroids or a history of interstitial lung disease.
9) Has an evidence of active, non-infectious pneumonitis.
10) Has a history of allogeneic tissue or solid organ transplant.
11) Has an active infection requiring systemic therapy.
12) Has a known history of HIV infection or any other relevant congenital or acquired immunodeficiency.
13) 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.
14) 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 >Grade 2, pulmonary embolism or symptomatic cerebrovascular events, or any other serious cardiac condition (eg, pericardial effusion or restrictive cardiomyopathy). Chronic atrial fibrillation on stable anticoagulant therapy is allowed.
15) Psychiatric illness/social circumstances that would limit compliance with study requirements and substantially increase the risk of AEs or has compromised ability to provide written informed consent.

Related Information

• Primary Sponsor: Nakayama Ippei
• Secondary ID(s): NCT04381650,2020-004325-23