A Study of TAK-676 as Single Agent and TAK-676 in Combination With Pembrolizumab in Adults With Advanced or Metastatic Solid Tumors

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Takeda Development Center Americas Inc.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

26 Jul 2023 → 31 Mar 2026

Decision date (initial)

2024-06-04

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Takeda Development Center Americas, Inc.

External identifiers

EU CT number

2023-505627-30-00

EudraCT number

2022-000528-39

WHO UTN

U1111-1241-4427

ClinicalTrials.gov

NCT04420884

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Pharmacokinetic, Pharmacodynamic, Therapy, Efficacy, Others, Dose response, Pharmacogenomic

Dose escalation:
• To determine the safety and tolerability of escalating doses of dazostinag administered as an SA or in combination with pembrolizumab in patients with advanced or metastatic solid tumors.

Japan safety lead-in:
• To determine the safety and tolerability of dazostinag in combination with pembrolizumab in Japanese patients with advanced or metastatic solid tumors.

Expansion phase:
• To determine the safety and tolerability of dazostinag in combination with pembrolizumab with or without chemotherapy in patients with previously untreated metastatic or unresectable, recurrent SCCHN.
• To determine the safety and tolerability of dazostinag in combination with pembrolizumab in patients with previously treated recurrent locally advanced or metastatic MSI-H/dMMR CRC and MSS/pMMR CRC.

Secondary objectives 4

1. Dose escalation: To assess the preliminary antitumor activity of dazostinag administered as an SA and in combination with pembrolizumab.
2. Japan Safety Lead-In: To assess the preliminary antitumor activity of dazostinag administred in combination with pembrolizumab in Japanese patients
3. Expansion phase: To assess the preliminary antitumor activity of dazostinag in combination with pembrolizumab with or without chemotherapy in previously untreated metastatic or unresectable, recurrent SCCHN patients.
4. Expansion phase: To assess the preliminary antitumor activity of dazostinag in combination with pembrolizumab in third-line or later recurrent locally advanced or metastatic MSI-H/dMMR CRC and third-line recurrent locally advanced or metastatic MSS/pMMR CRC patients.

Conditions and MedDRA coding

Solid Neoplasm

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 16

1. Adult male or female patients aged 18 years or older. • For Japan safety lead-in: Japanese who are living in Japan.
2. Capacity to give informed consent. Proxy consenting will only be allowed where permitted by local regulations or laws.
3. ECOG performance status of 0 to 1.
4. Patients to have a life expectancy of >12 weeks.
5. Dazostinag SA (dose escalation Part 1A): • Patients with histologically confirmed (cytological diagnosis is acceptable) advanced or metastatic solid tumors that have no standard therapeutic options or are intolerant to these therapies. Intolerant patients are those who have developed clinical or laboratory abnormalities that prevent continued drug administration as evaluated by the principal investigator at the time of screening.
6. Dazostinag in combination with pembrolizumab (dose escalation Parts 1B and Japan safety lead-in): • Patients with histologically confirmed (cytological diagnosis is acceptable) advanced or metastatic solid tumors that have no standard therapeutic options or are intolerant to them, including: – Tumors that have relapsed or are refractory to anti-PD-1/anti-PD-(L)1 therapy. • Refractory tumors are defined as those that progressed by either clinical or radiographic assessment at the first evaluation point after initiation of anti-PD-1/anti-PD-L1 treatment. • Relapsed tumors are defined as those that progressed by either clinical or radiographic assessment at any evaluation point thereafter. – Tumors that are naïve to anti-PD-(L)1 therapy, including but not limited to the following tumor types of interest: • Tumors with no health authority-approved indication for pembrolizumab use. • Tumors with limited response to anti-PD-(L)1 therapy and having a health authority-approved indication for pembrolizumab use.
7. For expansion phase only: • SCCHN (Part 2): - Patients with histologically confirmed metastatic or unresectable, recurrent SCCHN that is considered incurable by local therapies. Patients should not have had prior systemic therapy administered in the recurrent or metastatic setting. Systemic therapy which was completed more than 6 months before signing consent if given as part of multimodal treatment of locally advanced disease is allowed.- Anatomic subsites to be included are oral cavity, oropharynx, hypopharynx, larynx, nasal cavity, and paranasal sinuses . The exception to this is nasopharyngeal cancer and salivary gland tumors, which will not be included.- Patients with oropharyngeal cancer or tumors arising in the paranasal sinuses must agree to provide archival tissue for HPV testing or if known, HPV testing results and a 70% cutoff point must be provided. Alternatively, archival tissue or a fresh excisional or core needle biopsy (>=2 cores) is required for the determination of HPV status. If HPV status was previously tested using this method (CINtec® p16 Histology assay is preferred but not required), no additional testing is required..- For Part 2A, tumors must have a PD-L1 CPS ≥1. Patients must agree to provide fresh tumor biopsy for analysis from a core or excisional biopsy (fine needle aspirate is not sufficient) at screening for PD-L1 CPS assessment by a central laboratory. This specimen may be the diagnostic sample for patients with a new diagnosis of metastatic SCCHN. Patients for whom newly obtained samples cannot be obtained may submit an archived specimen only upon agreement from the Sponsor. Archival tissue can be obtained up to 90 days prior to screening provided there was no other treatment from the time of biopsy until the start of study treatment. For Part 2B, any CPS is eligible but fresh or archival tissue is required for confirmation of CPS status. .- For Part 2B, patients must be eligible to receive treatment with either cisplatin or carboplatin in combination with 5-FU per the treating physician. •CRC (Part 3): - Third-line or later MSI-H/dMMR CRC (Part 3A): Patients with histologically confirmed recurrent locally advanced or metastatic MSI-H/dMMR CRC whose disease has progressed on or following therapy with 1) an anti-PD-1 or PD-L1 antibody (ie, pembrolizumab) and 2) at least one1 line of combination chemotherapy including a fluoropyrimidine and irinotecan OR oxaliplatin with or without an anti-EGFR or anti-VEGFR monoclonal antibody (ie, cetuximab or bevacizumab). MSI-H/dMMR CRC patients must have received at least 6 weeks of prior treatment with an anti-PD-(L)1 antibody. Only one1 line of anti PD-(L)1 is permitted.- Third-line MSS/pMMR CRC (Part 3B): Patients with histologically confirmed recurrent locally advanced or metastatic MSS/pMMR CRC whose disease has progressed on or following therapy with 2 different lines of combination chemotherapy, including therapy with a fluoropyrimidine and irinotecan AND therapy with a fluoropyrimidine and oxaliplatin. Both lines of therapy may be given with or without an anti-EGFR or anti VEGFR monoclonal antibody (ie, cetuximab or bevacizumab). Patients with MSS/pMMR CRC must have progressed on or after combination chemotherapy regimens containing BOTH irinotecan AND oxaliplatin.- Patients with MSI-H/dMMR or MSS/pMMR CRC must have documented MSI/MMR status assessed by a Clinical Laboratory Improvements Amendment certified US sites) or an accredited (outside of the US) local laboratory using IHC and/or PCR or NGS assay.- Adequate tumor tissue available for central laboratory confirmation of MSI/MMR status. Note: confirmation of central test positivity is not required before treatment.- Patients with MSI-H/dMMR or MSS/pMMR CRC must have been treated with 2 prior lines of therapy in the recurrent locally advanced or metastatic setting.
8. Adequate bone marrow, renal, and hepatic functions, as determined by the following laboratory parameters: •For Part 1, Part 2A, and Parts 3A and 3B: ANC ≥1500/µL, platelet count ≥75,000/µL, and hemoglobin ≥8.0 g/dL without growth factor support for ANC or transfusion support for platelets within 14 days before the first study treatment dose. •For Part 2B: ANC ≥1500/µL, platelet count ≥100,000/µL, and hemoglobin ≥9.0 g/dL without growth factor support for ANC or transfusion support for platelets within 14 days before the first study treatment dose. •Total bilirubin ≤1.5 × the institutional ULN. For patients with Gilbert’s disease, ≤3 mg/dL. • Serum ALT and AST ≤3.0 × ULN. AST and ALT may be elevated up to 5 × ULN if their elevation can be reasonably ascribed to the presence of metastatic disease in liver. • Albumin ≥3.0 g/dL. • For Part 1, Part 2A, and Parts 3A and 3B: estimated creatinine clearance using the Cockcroft-Gault formula ≥30 mL/minute. For Part 2B: estimated creatinine clearance using the Cockcroft-Gault formula ≥60 mL/minute.
9. Left ventricular ejection fraction >50%, as measured by echocardiogram or multiple gated acquisition scan within 4 weeks before receiving the first dose of study drug.
10. Clinically significant toxic effects of previous therapy have recovered to Grade 1 (per NCI CTCAE Version 5.0) or baseline, except for alopecia, Grade 2 peripheral neuropathy, and/or autoimmune endocrinopathies with stable endocrine replacement therapy.
11. In dose escalation Part 1 (not applicable for the Japan safety lead-in), once peripheral evidence of dazostinag pharmacodynamic stimulation of the innate and/or adaptive immune system is observed in the blood and/or an imaging response ([CR]/[PR]) is observed in at least 1 patient, subsequent patients must: • Have at least 1 lesion amenable for biopsy. • Agree to have 2 tumor biopsies: 1 during the screening period and 1 while on dazostinag treatment. In dose expansion Parts 2 and 3 (with the exception of the safety lead-in in Part 2B), patients must be willing to consent to mandatory pretreatment and on-treatment tumor biopsy, if deemed safely accessible. In Parts 1, 2 and 3 once the target number of paired biopsies have been collected and analyzed to evaluate intra-tumor pharmacodynamics, additional paired pretreatment and on treatment biopsies will be optional, but not required.
12. Patients must have at least 1 RECIST v.1.1–evaluable measurable lesion. For the dose escalation phase (Part 1) only, nonmeasurable only disease is acceptable.
13. PK/pharmacodynamic blood must be drawn on a peripherally-inserted catheter. Dazostinag is preferentially administered through a central line, but peripheral infusion is acceptable. If a peripheral line is used for dazostinag and/or pembrolizumab infusion, it must be separate than the one1 used for PK/pharmacodynamic collection.
14. Female patients must be: • Postmenopausal (natural amenorrhea and not due to other medical reasons) for at least 1 year before the screening visit, OR • Surgically sterile, OR • If they are of childbearing potential, agree to practice 2 effective methods of contraception (see Section 8.9) at the same time, from the time of signing the informed consent through 180 days after the last dose of study drug(s), OR • Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the patient. – Note: Periodic abstinence (eg, calendar, ovulation, symptothermal, postovulation methods), withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception.
15. Male patients, even if surgically sterilized (ie, status postvasectomy), must: • Agree to practice effective barrier contraception (see Section 8.9) during the entire study treatment period and through 180 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 patient. – Note: Periodic abstinence (eg, calendar, ovulation, symptothermal, postovulation methods), withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception.
16. Written consent must be obtained.

Exclusion criteria 26

1. History of any of the following ≤6 months before first dose of study drug(s): congestive heart failure New York Heart Association Grade III or IV, (Appendix E)unstable angina, myocardial infarction, persistent hypertension ≥160/100 mm Hg despite optimal medical therapy, ongoing cardiac arrhythmias of Grade >2 (including atrial flutter/fibrillation or intermittent ventricular tachycardia), other ongoing serious cardiac conditions (eg, Grade 3 pericardial effusion or Grade 3 restrictive cardiomyopathy), or symptomatic cerebrovascular events. Chronic, stable atrial fibrillation on stable anticoagulation therapy, including low molecular weight heparin, is allowed.
2. QTcF >450 milliseconds (men) or >475 milliseconds (women) on a 12-lead ECG during the screening period.
3. Grade ≥2 hypotension (ie, hypotension for which nonurgent intervention is required) at screening or during C0D1 (for Japan safety lead-in only) and C1D1 predose assessment.
4. Oxygen saturation <92% on room air at screening or during C0D1 (for Japan safety lead-in only) and C1D1 predose assessment.
5. Patients treated with other STING agonists/antagonist and toll-like receptors agonists within the past 6 months.
6. Current history of pneumonitis, interstitial lung disease, severe chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, other restrictive lung diseases, acute pulmonary embolism, or Grade ≥2 pleural effusion or ascites not controlled by tap or requiring indwelling catheters.
7. History of brain and leptomeningeal metastasis unless: • Brain metastases are clinically and radiologically stable or improved (ie, ≥6 weeks) following surgery, whole-brain radiation, or stereotactic radiosurgery, AND • Off corticosteroids.
8. Ongoing Grade ≥2 infection or patients with Grade ≥2 fever of malignant origin.
9. Known history of uncontrolled autoimmune disorders, HIV infection, or other relevant congenital or acquired immunodeficiencies.
10. Chronic, active hepatitis (eg, patients with known hepatitis B surface antigen seropositive and/or detectable HCV-RNA). • Note: Patients who have positive hepatitis B core antibody can be enrolled but must have an undetectable serum hepatitis B virus-DNA. Patients who have positive hepatitis C virus antibody must have an undetectable HCV-RNA serum level. However, if the patient enrolls in the study, they will be monitored based on the local or institutional guidelines.
11. For patients in the dose escalation SA Part 1A only: refusal of standard therapeutic options.
12. For patients receiving pembrolizumab only: contraindication and/or intolerance to the administration of pembrolizumab. For patients receiving chemotherapy in Part 2B: contraindication and/or intolerance to the administration of both platinum agents (cisplatin and carboplatin) and/or 5-FU.
13. Any illness, metabolic dysfunction, physical examination finding, or clinical laboratory finding that give reasonable suspicion of a disease or condition that would contraindicate the use of an investigational drug or that would limit compliance with study requirements or compromise ability to provide written informed consent.
14. Patient has had any other prior or concurrent malignancy within 2 years prior to enrollment with the following exceptions: adequately treated localized basal cell or squamous cell carcinoma, or curatively treated in situ carcinoma of the cervix or breast. Other exceptions may be considered upon sponsor consultation.
15. Treatment with any investigational products and systemic anticancer drugs (including VEGF inhibitors), within 28 days or 5 half lives, whichever is shorter, before C1D1 of study drug(s).
16. Concurrent chemotherapy (except for Part 2B), immunotherapy (except for pembrolizumab in Part 1B, Part 2, and Part 3), biologic, or hormonal therapy (except for adjuvant endocrine therapy for a history of breast cancer). Concurrent use of hormones for noncancer-related conditions is acceptable (except for corticosteroid hormones, unless allowed per exclusion criterion 19).
17. Radiation therapy within 14 days (42 days for radiation to the lungs) and/or systemic treatment with radionuclides within 42 days before C1D1 of study drug(s). Patients with clinically relevant ongoing pulmonary complications from prior radiation therapy are not eligible.
18. Use of systemic corticosteroids or other immunosuppressive therapy, concurrently or within 7 days of C1D1 of study drug(s), with the following exceptions: • Topical, intranasal, inhaled, ocular, intra-articular, and/or other nonsystemic corticosteroids. • Premedications required for CT or MRI scans • Physiological doses of replacement steroid therapy (eg, for adrenal insufficiency). Refer to Section 8.7 for a list of allowed steroid therapy and doses. • For patients enrolled in Part 2B, chemotherapy premedication with steroids can be administered according to local standards of care practice.
19. Use of medications that are known clinical OATP1B1 and/or OATP1B3 inhibitors, concurrently or within 14 days of C1D1 of study drug(s). See Section 8.7 or Appendix H for a nonexhaustive list of the OATP1B1 and/or OATP1B3 inhibitors.
20. Receipt of live attenuated vaccine (eg, tuberculosis Bacillus Calmette-Guerin vaccine, oral polio vaccine, measles, rotavirus, yellow fever) within 28 days of C1D1 of study drug(s).
21. Recipients of allogeneic or autologous stem cell transplantation or organ transplantation.
22. Female patients who are lactating or have a positive serum/urine pregnancy test during the screening period or a positive serum/urine pregnancy test on Day 1 before first dose of study drug. In the very early stages of pregnancy, pregnancy tests may not be positive. If pregnancy is suspected based on a doctor's interview, the patient is not eligible. • Note: Female patients who are lactating will be eligible if they choose to discontinue breastfeeding before the first dose of study drug.
23. For Part 2 SCCHN only: (PD) within six months of completion of curatively intended systemic treatment for locoregionally advanced SCCHN.
24. Has a life expectancy of less than 3 months and/or has rapidly progressive disease (eg, tumor bleeding, uncontrolled tumor pain) in the opinion of the treating investigator.
25. Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2 or anti-CTLA-4 agent.
26. Patients with known dihydropyrimidine dehydrogenase (DPD) deficiency or thymidine phosphorylase gene (TYMP) mutations (Part 2B only).

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 5

1. Frequency and severity of TEAEs.
2. Number of patients with DLTs.
3. Number and percentage of patients with 1 or more treatment-emergent SAE.
4. Number and percentage of patients with 1 or more TEAE leading to dose modifications and treatment discontinuation.
5. Safety endpoints will be evaluated according to the (NCI CTCAE), Version 5.0.

Secondary endpoints 9

1. Dose escalation, Japan safety lead-in, and expansion phases:
2. Response assessments per (RECIST) v.1.1 (Eisenhauer et al. 2009) by investigator – ORR ([cCR] + [cPR]).
3. Response assessments per (RECIST) v.1.1 (Eisenhauer et al. 2009) by investigator. DCR (cCR + cPR + [SD] >6 weeks).
4. Response assessments per (RECIST) v.1.1 (Eisenhauer et al. 2009) by investigator. DOR.
5. Response assessments per (RECIST) v.1.1 (Eisenhauer et al. 2009) by investigator. TTR.
6. Expansion phase only: Response assessments per RECIST v.1.1 by investigator – PFS
7. Response assessments per RECIST v.1.1 by investigator. OS
8. Response assessments per RECIST v.1.1 by investigator. OS rate at 12 months
9. Response assessments per RECIST v.1.1 by investigator. OS rate at 6 months

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 6

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Takeda Development Center Americas Inc.

Sponsor organisation

Takeda Development Center Americas Inc.

Address

500 Kendall Street

City

Cambridge

Postcode

02142-1108

Country

United States

Scientific contact point

Organisation

Takeda Development Center Americas Inc.

Contact name

Jeffrey Raizer

Public contact point

Organisation

Takeda Development Center Americas Inc.

Contact name

Takeda

Third parties 16

Locations

4 EU/EEA countries · 16 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 57 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

4 submissions — initial application plus substantial / non-substantial modifications