TAK-676 + Pembrolizumab for Metastatic Cancer

(iintune-1 Trial)

Not currently recruiting at 90 trial locations

Overseen By Anthony Olszanski

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Takeda

Must not be taking: STING agonists, Toll-like agonists

Disqualifiers: Lung disease, Brain metastasis, Hepatitis, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: Unknown

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine the optimal dose of a new drug, dazostinag (also known as TAK-676), both alone and with pembrolizumab, for individuals with advanced solid tumors. It evaluates the safety of these drugs and any potential side effects. The trial consists of different parts, each focusing on specific cancer types, such as head and neck cancer and colorectal cancer. Suitable candidates have advanced cancer that has not responded to other treatments or cannot be treated with standard methods. As a Phase 1 trial, this research seeks to understand how the treatment works in people, offering participants the opportunity to be among the first to receive this new treatment.

Do I need to stop my current medications to join the trial?

The trial protocol does not specify if you must stop taking your current medications. However, you cannot use certain medications like systemic corticosteroids or immunosuppressive therapy within 7 days of starting the study drugs, and you should avoid medications that inhibit OATP1B1 and OATP1B3 within 14 days of starting. It's best to discuss your specific medications with the trial team.

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop taking your current medications. However, certain medications like systemic corticosteroids, immunosuppressive therapy, and specific inhibitors must be avoided before starting the trial. It's best to discuss your current medications with the trial team.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Studies have shown that the combination of dazostinag (also known as TAK-676) and pembrolizumab is generally safe. Previous research found that patients tolerated the treatment well, even at different doses. The main side effect, cytokine release syndrome (CRS), was mild to moderate and managed effectively.

For the combination of dazostinag, pembrolizumab, and chemotherapy, detailed safety information is not yet available. As the trial is in its early stages, researchers are still collecting data on safety and patient tolerance. Early-phase trials focus on ensuring treatments are safe before progressing to larger studies.

Overall, while some side effects are expected, current findings indicate that researchers are closely monitoring and managing the treatment's safety. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of TAK-676 and pembrolizumab for metastatic cancer because it introduces a novel approach to boosting the immune system's ability to fight cancer. Unlike standard chemotherapy, which directly targets and kills cancer cells, TAK-676 works by stimulating the body's innate immune response, potentially enhancing the effectiveness of pembrolizumab, an immune checkpoint inhibitor. This combination aims to improve outcomes for patients with challenging cancers, like squamous cell carcinoma of the head and neck and colorectal cancer, by leveraging the body's natural defenses in a new way. This innovative mechanism offers hope for better efficacy and fewer side effects compared to traditional treatments.

What evidence suggests that this trial's treatments could be effective for metastatic cancer?

Research has shown that pembrolizumab can help treat certain cancers. For instance, in cases of advanced melanoma, over one-third of patients remained alive ten years after starting treatment. About 39.6% of patients responded well, with many experiencing long-lasting benefits.

In this trial, participants will receive Dazostinag, also known as TAK-676, in combination with pembrolizumab. Dazostinag enhances the immune system's ability to fight cancer, and early studies suggest it is generally safe. The trial aims to evaluate the effectiveness of this combination in boosting the body's immune response. While specific results of this combination are still under study, the approach appears promising because both treatments work well together. ^{6 7 8 9 10}

Who Is on the Research Team?

Study Director

Principal Investigator

Takeda

Are You a Good Fit for This Trial?

Adults with advanced or metastatic solid tumors who haven't responded to standard treatments, or can't tolerate them, may join this trial. They should be in good physical condition (ECOG 0-1), have not received certain vaccines recently, and must not have active hepatitis or heart issues. Smokers and those with specific lung conditions cannot participate.

Inclusion Criteria

I have advanced cancer with no standard treatment options left or cannot tolerate them.

My side effects from previous treatments have mostly gone, except for possible hair loss, mild nerve pain, or hormone issues treated with stable medication.

My throat cancer cannot be removed by surgery and I haven't had systemic therapy for it in its advanced stage.

Exclusion Criteria

You are currently smoking.

I haven't taken STING or toll-like receptor treatments in the last 6 months.

I cannot take pembrolizumab due to adverse reactions or medical reasons.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose Escalation Phase

Participants receive escalating doses of Dazostinag alone and in combination with Pembrolizumab to determine safety and tolerability

54 months

Multiple visits (in-person)

Expansion Phase

Participants receive Dazostinag with Pembrolizumab, with or without chemotherapy, to evaluate efficacy in specific cancer types

54 months

Multiple visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

12 months

Follow-up visits (in-person)

What Are the Treatments Tested in This Trial?

Interventions

• 5-fluorouracil
• Pembrolizumab
• Platinum
• TAK-676

Trial Overview The study is testing TAK-676 alone and combined with Pembrolizumab to find the highest dose patients can take without severe side effects. It includes a phase where doses increase (dose escalation) followed by a phase that tests the chosen dose more broadly (dose expansion). Some will also receive chemotherapy drugs like Platinum and 5-fluorouracil.

How Is the Trial Designed?

Group I: Part 3B (Expansion Phase in CRC): Dazostinag + Pembrolizumab in MSS/pMMR CRC Experimental Treatment 2 Interventions

Dazostinag 5.0 mg, infusion, IV, will be administered in participants with microsatellite stable/mismatch repair proficient (MSS/pMMR) CRC at the identified dose level from Part 1 on Days 1, 8, and 15 in a 21-day cycle. along with pembrolizumab 200 mg infusion, IV, Q3W.

Group II: Part 3A (Expansion Phase in CRC): Dazostinag + Pembrolizumab in MSI-H/dMMR CRC Experimental Treatment 2 Interventions

Dazostinag 5.0 mg, infusion, IV, will be administered in participants with microsatellite instability-high /mismatch repair deficient (MSI-H/dMMR) colorectal cancer (CRC) at the identified dose level from Part 1 on Days 1, 8, and 15 in a 21-day cycle along with pembrolizumab 200 mg infusion, IV, Q3W.

Group III: Part 2B (SCCHN Dose Expansion Phase): Dazostinag + Pembrolizumab + Chemotherapy Experimental Treatment 4 Interventions

Dazostinag 5.0 mg, infusion, IV, will be administered in participants with SCCHN at the identified dose level from Part 1 on Days 1, 8, and 15 in a 21-day cycle. Pembrolizumab infusion, IV will be administered at 200 mg Q3W. Platinum-based chemotherapy comprising the combination of carboplatin (target area under the curve of 5 milligrams per milli Liters per minute (mg/mL/minute) \[AUC 5\]) or cisplatin (100 milligrams per square meter \[mg/m\^2\] Day 1 of each treatment cycle), and 5-fluorouracil (\[5-FU\]; 1000 mg/m\^2 per day for 4 consecutive days) Q3W for up to 6 cycles.

Group IV: Part 2A (SCCHN CPS ≥ 1 Dose Expansion and Optimization Phase): Dazostinag + Pembrolizumab Experimental Treatment 2 Interventions

Dazostinag 5.0 mg, infusion, IV, will be administered in participants with squamous cell carcinoma of head and neck (SCCHN) at the identified dose level from Part 1 on Days 1, 8, and 15 in a 21-day cycle along with pembrolizumab 200 mg infusion, IV, Q3W. Dose optimization may be performed in this phase.

Group V: Part 1B (Combination Dose Escalation Phase): Dazostinag + Pembrolizumab Experimental Treatment 2 Interventions

Dazostinag escalating doses (0.2 mg and above) in combination with pembrolizumab 200 mg, infusion, IV, once weekly on Days 1, 8 and 15 in each 21-day treatment cycle. Pembrolizumab 200 mg will be administered 1 hour prior to Dazostinag once every 3 weeks (Q3W). The dosing will be initiated when at least two dose levels (DLs) of Part 1A have been evaluated.

Group VI: Part 1 (Monotherapy Dose Escalation Phase): Dazostinag Safety Lead-in + Dazostinag SA [Part 1A] Experimental Treatment 1 Intervention

Safety Lead-in: Dazostinag 0.1 mg, infusion, intravenously (IV), once weekly, on Days 1, 8 and 15 in 21-day treatment cycles. Dazostinag SA Dose Escalation (Part 1A): Dazostinag single agent (SA), infusion, IV, once weekly on Days 1, 8 and 15 in each 21-day treatment cycles with escalating doses (0.2 mg and above). The dosing will be initiated in the Dazostinag SA Dose Escalation Phase based on the available safety and tolerability data from the Safety Lead-in.

Group VII: Arm B: Japan Safety Lead-in Dazostinag Transitioned to Pembrolizumab Experimental Treatment 2 Interventions

Dazostinag 5.0 mg, infusion, IV, as an SA once on Day 1 in Cycle 0 (cycle length=7 days) in Japanese participants with advanced or metastatic solid tumors based on confirmation of tolerability in Arm A. Following Cycle 0 (7 days), participants will be transitioned to the same dose level of dazostinag on Days 1, 8, and 15 of each 21-day cycle in combination with pembrolizumab administered Q3W, IV, on Day 1 in each 21-day cycle. Additional dose levels of dazostinag (such as ≥ 7.0 mg) in combination with pembrolizumab (200 mg, Q3W) may be explored in the Safety Lead-in.

Group VIII: Arm A: Japan Safety Lead-in Dazostinag + Pembrolizumab Experimental Treatment 2 Interventions

Dazostinag 5.0 mg, infusion, IV, in Japanese participants with advanced or metastatic solid tumors on Days 1, 8, and 15 in each 21-day cycle in combination with pembrolizumab 200 mg administered Q3W, IV, on Day 1 in each 21-day cycle. Additional dose levels of Dazostinag (such as 14.0 mg) in combination with pembrolizumab (200 mg, Q3W) may be explored in the Safety Lead-in.

Pembrolizumab is already approved in United States, European Union, United Kingdom for the following indications:

Approved in United States as KEYTRUDA for:

• Head and neck squamous cell carcinoma (HNSCC) with PD-L1 CPS ≥1
• Melanoma
• Non-small cell lung cancer (NSCLC)
• Urothelial carcinoma
• Colorectal cancer
• Gastric cancer
• Hepatocellular carcinoma
• Renal cell carcinoma
• Cervical cancer
• Endometrial carcinoma

Approved in European Union as KEYTRUDA for:

• Head and neck squamous cell carcinoma (HNSCC) with PD-L1 CPS ≥1
• Melanoma
• Non-small cell lung cancer (NSCLC)
• Urothelial carcinoma
• Colorectal cancer
• Gastric cancer
• Hepatocellular carcinoma
• Renal cell carcinoma
• Cervical cancer
• Endometrial carcinoma

Approved in United Kingdom as KEYTRUDA for:

• Untreated metastatic or unresectable recurrent head and neck squamous cell carcinoma (HNSCC) with PD-L1 CPS ≥1

Who Is Running the Clinical Trial?

Takeda

Lead Sponsor

Trials

1,255

Recruited

4,219,000+

Dr. Naoyoshi Hirota

Takeda

Chief Medical Officer since 2020

MD from University of Tokyo

Christophe Weber

Takeda

Chief Executive Officer since 2015

PhD in Molecular Biology from Université de Montpellier

Published Research Related to This Trial

A systematic review of four trials involving 3425 patients found that lower doses of pembrolizumab (2 mg/kg every 3 weeks) are equally effective as higher doses (10 mg/kg) in treating advanced melanoma and non-small-cell lung cancer (NSCLC).

The safety profile of pembrolizumab was similar across different doses, suggesting that the lower dose may be sufficient for routine treatment without compromising efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evaluation of efficacy and safety of different pembrolizumab dose/schedules in treatment of non-small-cell lung cancer and melanoma: a systematic review. Abdel-Rahman, O.[2018]

In a phase II trial involving 15 patients with resectable non-small cell lung cancer (NSCLC), neoadjuvant treatment with pembrolizumab showed a major pathologic response in 27% of patients, indicating promising antitumor activity before surgery.

The treatment was found to be feasible and safe, with only 33% of patients experiencing moderate adverse events, and no postoperative mortality, suggesting that pembrolizumab does not compromise surgical outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neoadjuvant anti-programmed death-1 immunotherapy by pembrolizumab in resectable non-small cell lung cancer: First clinical experience. Eichhorn, F., Klotz, LV., Kriegsmann, M., et al.[2022]

In the KEYNOTE-189 study, first-line treatment with pembrolizumab combined with pemetrexed-platinum significantly improved overall survival (OS) to a median of 22.0 months compared to 10.7 months for the placebo group, indicating a strong efficacy in treating metastatic nonsquamous non-small-cell lung cancer (NSCLC).

The combination therapy also resulted in a median progression-free survival (PFS) of 9.0 months versus 4.9 months for placebo, with benefits observed regardless of tumor PD-L1 expression or the presence of liver/brain metastases, while maintaining a similar incidence of serious adverse events between the two groups.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Updated Analysis From KEYNOTE-189: Pembrolizumab or Placebo Plus Pemetrexed and Platinum for Previously Untreated Metastatic Nonsquamous Non-Small-Cell Lung Cancer. Gadgeel, S., Rodríguez-Abreu, D., Speranza, G., et al.[2021]

In a phase 3 trial involving 305 patients with advanced non-small-cell lung cancer (NSCLC) expressing PD-L1, pembrolizumab significantly improved median progression-free survival to 10.3 months compared to 6.0 months with chemotherapy, indicating its efficacy as a treatment option.

Patients receiving pembrolizumab also experienced fewer treatment-related adverse events (73.4% vs. 90.0% for chemotherapy), highlighting its safety profile alongside its effectiveness in prolonging survival.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab versus Chemotherapy for PD-L1-Positive Non-Small-Cell Lung Cancer. Reck, M., Rodríguez-Abreu, D., Robinson, AG., et al.[2022]

Pembrolizumab, an anti-PD-1 antibody, has shown significant efficacy in treating advanced melanoma, demonstrating superior progression-free survival compared to chemotherapy in Phase II trials and improved overall survival in Phase III trials.

The treatment is generally well tolerated with a favorable safety profile, though common side effects include fatigue and rash, while less frequent but serious immune-related adverse events can occur.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab in the management of metastatic melanoma. Spain, L., Younger, E., Hatipoglu, E., et al.[2020]

The maximum tolerated doses (MTDs) for the combination of pembrolizumab and trametinib were established, with concurrent dosing showing a lower objective response rate (0%) compared to intermittent dosing (27%).

While the combination treatment had manageable safety profiles, with 31% of patients experiencing grade 3/4 treatment-related adverse events in the concurrent group, the overall antitumor activity was limited, suggesting that this combination may not be highly effective for solid tumors and BRAF wild-type melanoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

KEYNOTE-022: Pembrolizumab with trametinib in patients with BRAF wild-type melanoma or advanced solid tumours irrespective of BRAF mutation. Maio, M., Carlino, MS., Joshua, AM., et al.[2022]

In a long-term study of 123 patients with advanced nonsquamous NSCLC, the combination of pembrolizumab with pemetrexed-carboplatin significantly improved the objective response rate (58% vs. 33%) and progression-free survival (24.5 months vs. 9.9 months) compared to chemotherapy alone.

Patients who completed 2 years of pembrolizumab treatment had a remarkable 92% survival rate at the data cutoff, indicating a durable clinical benefit, while the safety profile remained manageable with no new safety concerns identified.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-Term Overall Survival From KEYNOTE-021 Cohort G: Pemetrexed and Carboplatin With or Without Pembrolizumab as First-Line Therapy for Advanced Nonsquamous NSCLC. Awad, MM., Gadgeel, SM., Borghaei, H., et al.[2021]

A 45-year-old male with metastatic melanoma experienced severe immune-related adverse events from ipilimumab, leading to its discontinuation, but successfully transitioned to pembrolizumab.

After over 20 months of treatment with pembrolizumab, the patient has shown no major toxicities and has achieved an ongoing partial response, suggesting that pembrolizumab may be a safe and effective option for patients with prior severe adverse events from other immunotherapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab in a BRAF-mutant metastatic melanoma patient following a severe immune-related adverse event with ipilimumab. Aya, F., Fernández-Martínez, A., Gaba, L., et al.[2017]

A 68-year-old patient with stage IV lung adenocarcinoma showed an unexpected positive response to paclitaxel after failing treatment with pembrolizumab, an anti-PD-1 immunotherapy.

The patient experienced a response duration of over fourteen months with paclitaxel, suggesting that combining or sequencing chemotherapy with immunotherapy may enhance treatment effectiveness in certain cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Prolonged response with paclitaxel after immunotherapy by pembrolizumab in lung cancer]. Zapata, E., Mennecier, B., Leduc, C., et al.[2017]

Pembrolizumab, a PD-1 inhibitor, has demonstrated clinical effectiveness in treating various solid tumors, particularly in patients with PD-L1-positive non-small-cell lung cancer and unresectable/metastatic melanoma.

Early-phase trials and ongoing studies are focused on further confirming the clinical benefits of pembrolizumab in thoracic malignancies, highlighting its potential as a significant treatment option in cancer therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab for the treatment of thoracic malignancies: current landscape and future directions. Karim, S., Leighl, N.[2017]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT01295827

NCT01295827 | Study of Pembrolizumab (MK-3475) in ... The study will investigate the safety, tolerability, and efficacy of pembrolizumab (2 mg/kg and 10 mg/kg) in participants with advanced or metastatic MEL.

2. merck.com merck.com/news/ten-year-data-for-mercks-keytruda-pembrolizumab-demonstrates-sustained-overall-survival-benefit-versus-ipilimumab-in-advanced-melanoma/

Ten-Year Data for Merck's KEYTRUDA® (pembrolizumab ... At 10 years, more than one-third (34.0%) of patients with advanced melanoma were alive after treatment with KEYTRUDA, compared to 23.6% of patients treated ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6527794/

Clinical utility of pembrolizumab in the management of ... The ORR with pembrolizumab across studies was 39.6% with 78% of responses lasting ≥6 months. These innovative data led to an FDA granted accelerated approval ...

4. keytrudahcp.com keytrudahcp.com/efficacy/

Efficacy Data for KEYTRUDA® (pembrolizumab) The most common adverse reactions (≥20%) with KEYTRUDA were nausea (56%), fatigue (56%), constipation (35%), diarrhea (31%), decreased appetite (28%), rash (25 ...

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7706128/

Efficacy of pembrolizumab for advanced/metastatic ... With pembrolizumab treatment, either alone or in combination, the progression-free survival (PFS) was 5.73 months; 12-, 24-, and 60-month PFS rate were 44%, 27% ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT04420884

NCT04420884 | A Study of Dazostinag as Single Agent ... The main aim of this study is to check if people with advanced solid tumors have side effects from dazostinag, and to check how much dazostinag they can ...

7. annalsofoncology.org annalsofoncology.org/article/S0923-7534(24)02574-2/fulltext

996MO Dazostinag (TAK-676) alone and in combination ... Dazo IV had a manageable safety profile, as SA and with pembro, across all dose levels. CRS was grade 1–2 and well managed.

8. dana-farber.org dana-farber.org/clinical-trials/20-236

An Open-label, Dose Escalation, Phase 1/2 Study to ... The main aim of this study is to check if people with advanced solid tumors have side effects from dazostinag, and to check how much dazostinag they can ...

9. annalsofoncology.org annalsofoncology.org/article/S0923-7534(23)03005-3/fulltext

1029P Dazostinag (TAK-676) alone and in combination ... Preliminary safety, PK/PD data, and anti-tumor activity support the declaration of the RDE of dazostinag 5 mg + pembro 200 mg. Expansion cohorts in colorectal ...

10. clinicaltrials.ucsd.edu clinicaltrials.ucsd.edu/trial/NCT04420884

UCSD Solid Neoplasms Trial → Dazostinag as Single Agent ... The main aim of this study is to check if people with advanced solid tumors have side effects from dazostinag, and to check how much dazostinag they can ...