| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Advanced or Metastatic Solid Tumors |
|
| E.1.1.1 | Medical condition in easily understood language |
| Advanced or Metastatic Solid Tumors |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10065252 |
| E.1.2 | Term | Solid tumor |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Phase 1b:
• To determine the safety and tolerability of TAK-981 in combination with pembrolizumab in patients with select solid tumor indications.
• To establish the recommended Phase 2 dose (RP2D).
Phase 2:
• To evaluate the preliminary efficacy of TAK-981 at the RP2D in combination with pembrolizumab in patients with select solid tumor indications.
|
|
| E.2.2 | Secondary objectives of the trial |
- To characterize the PK of TAK-981 in combination with pembrolizumab.
Phase 1b:
• To determine the MTD and/or pharmacologically active dose (PAD) of TAK-981 when administered in combination with pembrolizumab.
• To assess the preliminary antitumor activity of TAK-981-pembrolizumab combination.
• To assess target engagement of TAK-981 (SUMO-TAK-981 adduct formation) and SUMOylation pathway inhibition in blood.
Phase 2:
• To evaluate the efficacy of TAK-981 in combination with pembrolizumab in select solid tumors as measured by disease control rate (DCR), durable response rate (DRR), DOR, time to response (TTR), time to progression (TTP), PFS, and OS.
• To evaluate the safety and tolerability of TAK-981 in combination with pembrolizumab.
• To collect PK data to contribute to population PK and exposure-response (safety/efficacy) analysis. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1.Adult male or female patients aged 18 years or older.
2.Be willing and able to provide written informed consent for the study.
3.Have a histologically or cytologically documented, advanced (metastatic and/or unresectable) cancer as listed below that is incurable:
• A: Non-squamous NSCLC.
• B: Cervical cancer.
• C: MSS-CRC.
• D: Cutaneous melanoma.
• E: Squamous NSCLC.
• F: Small cell lung cancer.
• G: HNSCC.
• H: MSI-H/dMMR CRC.
Note: For further details, please refer to protocol.
4.Have 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.
5.Patients in Phase 2 expansion cohorts must have a PD-L1 result in tumor tissue obtained from an FDA-approved PD-L1 test.
6.Willing to consent to mandatory pre-treatment fresh tumor biopsy for Phase 2.
7.Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) Performance Scale.
8.Demonstrate adequate organ function as described below:
A.Platelet count ≥75.0 × 109/L.
B.Absolute neutrophil count (ANC) ≥1.0 × 109/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 × upper limit of normal (ULN), <5.0 times the ULN if liver enzyme elevations are due to liver metastases; bilirubin ≤1.5 × ULN. Patients with Gilbert's syndrome may have a bilirubin level >1.5 × ULN, per discussion between the investigator and the medical monitor.
9.Left ventricular ejection fraction (LVEF) ≥40%; as measured by echocardiogram (ECHO) or multiple-gated acquisition (MUGA) scan.
10.Have recovered to Grade 1 or baseline from all toxicity associated with previous therapy or have the toxicity established as sequela.
11.Women of childbearing potential must have a negative serum/urine pregnancy test within 72 hours prior to receiving the first dose of study medication.
12.Female patients must meet 1 of the following:
A.Postmenopausal for at least 1 year before the screening visit, or
B.Surgically sterile, or
C.If they are of childbearing potential, agree to practice 1 highly effective method and 1 additional effective (barrier) method of contraception at the same time, from the time of signing of the ICF through 6 months after the last dose of study, or
D.Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the patient. (Periodic abstinence [eg, 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.)
13.Male patients, even if surgically sterilized (ie, status postvasectomy) must agree to 1 of the following:
A.Agree to practice effective barrier contraception during the entire study treatment period and through 6 months after the last dose of study drug, or
B.Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the patient. (Periodic abstinence [eg, 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.)
14.Must be willing and able to comply with clinic visits and procedures outlined in the study protocol. |
|
| E.4 | Principal exclusion criteria |
1. Received 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. Received extended field radiotherapy ≤4 weeks before the start of treatment (≤7 days for limited field radiation for palliation outside the chest or brain).
3. 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). Patients 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.
4. 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 patient is not on active anticancer therapy.
5. Major surgery ≤14 days from the first dose of study drug and not recovered fully from any complications from surgery.
6. Prior treatment with TAK-981.
7. Hypersensitivity to TAK-981, pembrolizumab, or any component of the drug product.
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. History of immune-related AEs related to treatment with immune CPIs that required treatment discontinuation.
10. Receiving or requires the continued use of medications that are known to be strong or moderate inhibitors and inducers of CYP3A4/5 and strong P-glycoprotein (Pgp) inhibitors. To participate in this study, such patients should discontinue use of such agents for at least 2 weeks (1 week for CYP3A4/5 and Pgp inhibitors) before receiving a dose of TAK-981.
11. Receipt of any live vaccine within 4 weeks of initiation of study treatment.
12. 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 (eg, 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.
13. History of noninfectious pneumonitis that required steroids or a history of interstitial lung disease.
14. Has evidence of active, noninfectious pneumonitis.
15. History of allogeneic tissue or solid organ transplant.
16. Has active infection requiring systemic therapy.
17. Known history of HIV infection or any other relevant congenital or acquired immunodeficiency.
18. Known hepatitis B virus surface antigen seropositive or detectable hepatitis C infection viral load.
19. 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.
20. 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.
21. Female patients who are pregnant or lactating and breastfeeding. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Phase 1b:
-Frequency, severity, and duration of TEAEs and laboratory abnormalities for all dose groups according to the NCI CTCAE, Version 5.0, except CRS that will be graded according to American Society for Transplantation and Cellular Therapy (ASTCT) Consensus Grading for CRS.
-Occurrence of DLTs within the first 21 days of treatment in Cycle 1.
Phase 2:
-ORR (CR + PR) as assessed by the investigator according to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST, Version 1.1). |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
-TAK-981 plasma concentration-time data.
Phase 1b:
-ORR, DCR, DRR, DOR, TTR, TTP, and PFS as assessed by the investigator according to RECIST, Version 1.1 and the RECIST consensus guideline developed by the RECIST Working Group for the use of modified RECIST, Version 1.1 in cancer immunotherapy
trials (iRECIST).
-TAK-981-SUMO adduct formation and SUMO pathway inhibition in blood.
Phase 2:
-Frequency, severity, and duration of TEAEs and laboratory abnormalities for all dose groups according to the NCI CTCAE, Version 5.0, except CRS that will be graded according to ASTCT Consensus Grading for CRS.
-DCR, DRR, DOR, TTR, TTP, PFS, and OS as assessed by the investigator according to RECIST, Version 1.1 and iRECIST; ORR as assessed by the investigator according to iRECIST. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| 8 cohorts with select cancers are enrolled, please refer to protocol for details. |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 8 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 12 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Switzerland |
| Ukraine |
| Brazil |
| China |
| Japan |
| Latvia |
| Lithuania |
| Poland |
| Serbia |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| The end of study will occur when all patients have had the opportunity to complete 24 months of treatment; have been followed for survival for a minimum of 12 months after the last patient has been discontinued or completes treatment; until all patients have died, withdrawn consent, or are lost to follow-up; or the study is terminated (whichever occurs first). |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 1 |
| E.8.9.1 | In the Member State concerned days | 28 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 1 |
| E.8.9.2 | In all countries concerned by the trial days | 28 |
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