| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
Advanced and Metastatic solid tumors are masses of abnormal tissue growth that originate in organs or soft tissues that have spread to other parts of body and cannot be controlled with treatment.
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| 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 | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| 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 |
Primary Objectives:
Dose escalation:
To determine the safety and tolerability of escalating doses of TAK-676 administered as an SA or in combination with pembrolizumab in patients with advanced or metastatic solid tumors.
Expansion phase:
To determine the safety and tolerability of TAK-676 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 TAK-676 in combination with pembrolizumab in patients with previously treated recurrent locally advanced or metastatic MSI-H/dMMR CRC and MSS/pMMR CRC. |
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| E.2.2 | Secondary objectives of the trial |
Dose escalation:
To determine PAD and RDE of TAK-676 and characterize the single- and multiple-dose PK of TAK-676 administered as an SA and in combination with pembrolizumab. To assess the preliminary antitumor activity of TAK-676 administered as an SA and in combination with pembrolizumab.
To assess STING agonism gene signature induced by TAK-676 in blood as evidence of pharmacodynamic modulation.
To evaluate the TAK-676-mediated impact on tumor T-cell infiltration following TAK-676 administration in combination with pembrolizumab.
Expansion phase:
To confirm the RP2D of TAK-676 and characterize the single- and multiple-dose PK of TAK-676 administered in combination with pembrolizumab with or without chemotherapy.
To assess the preliminary antitumor activity of TAK-676 in combination with pembrolizumab with or without chemotherapy in previously untreated metastatic or unresectable, recurrent SCCHN patients.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.
2. TAK-676 SA (dose escalation Part 1A):
With histologically confirmed advanced or metastatic solid tumors that have no standard therapeutic options or are intolerant to these therapies.
3. TAK-676 in combination with pembrolizumab (dose escalation Part 1B)
With histologically confirmed 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-programmed cell death protein 1 (anti-PD-(L)1)/anti-programmed cell death ligand 1
• Tumors that are naive to anti-PD-1/ anti-PD-(L)1 therapy.
4. For expansion phase only:
• SCCHN (Part 2):
• Participants with histologically confirmed (cytological diagnosis is acceptable) metastatic or recurrent, unresectable SCCHN that is considered incurable by local therapies. Participants 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 (maxillary, ethmoid, sphenoid, and frontal). The exception to this is nasopharyngeal cancer and salivary gland tumors, which will not be included.
• Participants with oropharyngeal cancer or tumors arising in the paranasal sinuses (maxillary, ethmoid, sphenoid, and frontal) must agree to provide archival tissue for human papilloma virus (HPV) testing
• For Part 2A, tumors must have a PD-L1 combined positive score (CPS)
≥1. For Part 2B, any CPS is eligible.
• For Part 2B, participants must be eligible to receive treatment with either cisplatin or carboplatin in combination with 5-fluorouracil (5FU) per the treating physician.
5. CRC (Part 3):
• Third-line or later MSI-H/dMMR CRC (Part 3A): Participants with histologically confirmed (cytological diagnosis is acceptable) recurrent locally advanced or metastatic MSI-H/dMMR CRC whose disease has progressed on or following therapy with 1) an antiPD-1 or PD-L1 antibody (ie, pembrolizumab) and 2) at least one line of combination chemotherapy including a fluoropyrimidine and irinotecan OR oxaliplatin with or without an anti- epidermal growth factor receptor (EGFR) or anti-vascular endothelial growth factor (VEGFR) monoclonal antibody (ie, cetuximab or bevacizumab). MSI-H/dMMR CRC participants must have received at least 6 weeks of prior treatment with an anti-PD-1 or PD-(L)1 antibody.
•Third-line MSS/pMMR CRC (Part 3B): Participants with histologically confirmed (cytological diagnosis is acceptable) 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). Participants with MSS/pMMR CRC must have progressed on or after combination chemotherapy regimens
containing BOTH irinotecan AND oxaliplatin.
• Participants with MSI-H/dMMR or MSS/pMMR CRC must have MSI/MMR status assessed by certified/accredited lab.
• Participants 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.
6. Adequate bone marrow, renal, hepatic and cardiac functions.
7. Left ventricular ejection fraction (LVEF) >50%, as measured by echocardiogram or multiple-gated acquisition (MUGA) scan within 4 weeks before receiving the first dose of study drug.
8. Clinically significant toxic effects of previous therapy have recovered to Grade 1 (per NCI CTCAE Version 5.0) or baseline
9. In dose escalation Part 1, once peripheral evidence of TAK-676 pharmacodynamic stimulation of the innate and/or adaptive immune system is observed in the blood and/or clinical response/partial response (CR/PR) is observed in at least 1 participant, subsequent participants must:
• Have at least 1 lesion amenable for biopsy.
• Agree to have 2 tumor biopsies: 1 during the screening period and 1 while on TAK-676 treatment.
10. 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.
11. Pharmacokinetic (PK)/pharmacodynamic blood must be drawn on a peripherally-inserted catheter. TAK-676 is preferentially administered through a central line, but peripheral infusion is acceptable. If a peripheral line is used for TAK-676 and/or pembrolizumab infusion, it must be separate than the one used for PK/pharmacodynamic collection.
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| E.4 | Principal exclusion criteria |
1. Corrected QT interval by Fredericia (QTcF) greater than (>) 450 milliseconds (men) or >475 milliseconds (women) on a 12-lead electrocardiogram (ECG) during the screening period.
2. Grade greater than or equal to (>=) 2 hypotension (that is, hypotension for which nonurgent intervention is required) at screening or during Cycle 1 Day 1 (C1D1) predose assessment.
3. Oxygen saturation less than (<) 92 percent (%) on room air at screening or during C1D1 predose assessment.
4. Treated with other STING agonists/antagonist and toll-like receptors agonists within the past 6 months.
5. Active vaping within 90 days of C1D1 of study drug(s).
6. Active smoking.
7. 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.
8. History of brain and leptomeningeal metastasis unless:
• Clinically and radiologically stable or improved (that is, >=6 weeks) after prior surgery, whole-brain
radiation, or stereotactic radiosurgery, AND
• Off corticosteroids.
9. Ongoing Grade >= 2 infection or participants with Grade >=2 fever of
malignant origin.
10. Chronic, active hepatitis (example: participants with known hepatitis B
surface antigen seropositive and/or detectable hepatitis C virus [HCV]RNA).
11. For participants in the dose escalation SA Part 1A only: refusal of
standard therapeutic options.
12. For participants receiving pembrolizumab only: contraindication and/or
intolerance to the administration of pembrolizumab.
13. For participants receiving chemotherapy in Part 2B: contraindication
and/or intolerance to the administration of both platinum agents (cisplatin and carboplatin) and/or 5-FU.
14. 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 16.
15. 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). Participants with clinically relevant ongoing pulmonary complications from prior radiation therapy are not eligible.
16. 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.
• Physiological doses of replacement steroid therapy (example: for adrenal insufficiency).
• For participants enrolled in Part 2B, chemotherapy premedication with steroids can be administered according to local standards of care practice.
17. Use of medications that are known clinical organic anion-transporting polypeptide B1 (OATP1B1) and/or OATP1B3 inhibitors, concurrently or within 14 days of C1D1 of study drug(s).
18. Receipt of live attenuated vaccine (eg, tuberculosis Bacillus CalmetteGuerin vaccine, oral polio vaccine, measles, rotavirus, yellow fever) within 28 days of C1D1 of study drug(s).
19. Recipients of allogeneic or autologous stem cell transplantation or organ transplantation.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary endpoints are:
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.
Safety endpoints will be evaluated according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), Version 5.0.
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
The primary analyses for the primary endpoint will be conducted after all patients enrolled in the study have had the opportunity to complete 24 months of treatment with TAK-676.
Up to approximately 54 months.
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| E.5.2 | Secondary end point(s) |
Dose escalation and expansion phases:
1. PK parameters after administration of TAK-676:
– Cmax.
– Time of first occurrence of Cmax (tmax).
– Area under the concentration-time curve from time 0 to time t (AUCt).
– Area under the concentration-time curve from time 0 to infinity (AUC∞).
– Terminal disposition phase half-life (t1/2z).
– Total clearance after intravenous administration (CL).
– Vss.
– Renal clearance (CLR) and percentage of dose excreted in urine during 24 hours after dosing.
– Renal clearance as a percentage of total clearance (CLR/CL [%]).
– Percentage of dose excreted in feces during 24 hours after dosing.
2. Response assessments per Response Evaluation Criteria in Solid Tumors (RECIST) v.1.1 (Eisenhauer et al. 2009) by investigator.
– ORR (confirmed complete response [cCR] + confirmed partial response [cPR]).
– Disease control rate (DCR) (cCR + cPR + stable disease [SD] >6 weeks).
– Duration of response (DOR).
– Time to response (TTR).
3. Upregulation of TAK-676–induced STING agonism gene expression signature in peripheral blood.
4. Evaluation of T-cell infiltration upon TAK-676 treatment (parts 1A, 1B, 2 and 3).
5. Genomic, transcriptomic and protein expression analyses of baseline and on-treatment tumor tissue (parts 1A, 1B, 2 and 3).
Expansion phase only:
1. Response assessments per RECIST v.1.1 by investigator
– Progression-free survival (PFS)
– OS
– OS rate at 12 months
– OS rate at 6 months
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Dose Escalation and Expansion Phases: Cycle 1 Days 1, 8 and 15: pre-infusion and at multiplepoints (up to 24 hours) post-infusion and at Day 1 for further cycles up to 54 months (Cycle length=21 days)]
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| 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 | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | No |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
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| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | Yes |
| 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 | No |
| 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 | 6 |
| 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 | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 20 |
| 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 |
| Puerto Rico |
| Canada |
| China |
| Israel |
| Japan |
| United Kingdom |
| United States |
| Austria |
| Belgium |
| France |
| Poland |
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| E.8.7 | Trial has a data monitoring committee | No |
| 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
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| The study will be completed at the time of primary analyses |
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | |
| E.8.9.1 | In the Member State concerned months | 63 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial months | 63 |
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