Clinical trial NCT04420884: A Study of Dazostinag as Single Agent and Dazostinag in Combination With Pembrolizumab in Adults With Advanced or Metastatic Solid Tumors
Official title: An Open-label, Dose Escalation, Phase 1/2 Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of TAK-676 as a Single Agent and in Combination With Pembrolizumab in Adult Patients With Advanced or Metastatic Solid Tumors
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE1
PHASE2
Conditions: Solid Neoplasms
Keywords: Drug Therapy
Lead sponsor: Takeda
Sponsor class: INDUSTRY
First posted: 2020-06-09
Enrollment: 248
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

Brief summary: 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 receive without getting significant side effects from it when given alone and in combination with pembrolizumab. The study will be conducted in two phases including a dose escalation phase and a dose expansion phase. In the dose escalation phase, escalating doses of dazostinag are being tested alone and in combination with pembrolizumab to treat participants who have advanced or metastatic solid tumors. In the dose expansion phase, dazostinag will be studied with pembrolizumab with or without chemotherapy in participants with untreated metastatic or recurrent, unresectable squamous cell carcinoma of head and neck (SCCHN) and in combination with pembrolizumab in third-line or later recurrent locally advanced or metastatic microsatellite instability-high/mismatch repair deficient (MSI-H/dMMR) and third-line recurrent locally advanced or metastatic microsatellite stable/mismatch repair proficient (MSS/pMMR) colorectal cancer (CRC).

Detailed description: The drug being tested in this study is called dazostinag. Dazostinag is being tested to treat people who have advanced or metastatic solid tumors.

The study will enroll approximately 374 participants. Part 1 consists of an initial Safety Lead-in to Dose Escalation Phase; Part 2 and Part 3 compose the Expansion Phase in 2 specific indications namely, previously untreated metastatic or recurrent, unresectable SCCHN (Part 2) and third-line or later recurrent locally advanced or metastatic MSI-H/dMMR and third-line recurrent locally advanced or metastatic MSS/pMMR CRC (Part 3). Participants will be assigned to the following treatment groups in the respective Phases of the study:

* Part 1 (Dose Escalation Phase): Safety Lead-in + Dazostinag single agent (SA) \[Part 1A\] Dazostinag 0.1 milligram (mg) in the Safety Lead-in followed by Dazostinag as escalating doses (0.2 mg and above) in Part 1A
* Part 1B (Combination Dose Escalation Phase): Dazostinag as escalating doses (0.2 mg and above) + Pembrolizumab
* Japan Safety Lead-in: Dazostinag SA 5.0 mg in the Safety Lead-in± Pembrolizumab in Arms A and B. Additional dose levels of Dazostinag (such as 14.0 mg) in combination with pembrolizumab may be explored during the Japan safety lead-in considering recommended dose for expansion (RDE1) as 5.0 mg and dose optimization.

Once a safe dose is recommended from Part 1, participants of select advanced or metastatic solid tumors will receive dazostinag in below defined cohorts in the expansion phase:

* Part 2A (SCCHN Combined Positive Score \[CPS\] ≥ 1 Dose Expansion Phase): Dazostinag + Pembrolizumab\*
* Part 2B (SCCHN Dose Expansion Phase): Dazostinag + Pembrolizumab + Chemotherapy
* Part 3A (Expansion Phase in CRC): Dazostinag + Pembrolizumab in MSI-H/dMMR CRC
* Part 3B (Expansion Phase in CRC): Dazostinag + Pembrolizumab in MSS/pMMR CRC

This multi-center trial will be conducted worldwide. The overall time to participate in this study is 68 months. Participants will make multiple visits to the clinic, including 30 days after last dose of study drug for a follow-up assessment. Participants in Parts 2 and 3 will be followed for survival for up to 12 months after the last dose of study drug.

Eligibility criteria: Inclusion Criteria:

1. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.
2. Dazostinag SA (dose escalation Part 1A):

   o With histologically confirmed (cytological diagnosis is acceptable) advanced or metastatic solid tumors that have no standard therapeutic options or are intolerant to these therapies.
3. Dazostinag in combination with pembrolizumab (dose escalation Parts 1B and Japan safety lead-in):

   * 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-programmed cell death ligand protein 1 (anti PD-(L)-1) therapy.
   * Tumors that are naive to 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 or if known, HPV testing results (using CINtec® p16 Histology assay is preferred but not required) 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. Archival tissue can be obtained up to 90 days prior to screening. Samples that are older than 90 days at screening may be used after consultation with the sponsor.
   * For Part 2A, tumors must have a PD-L1 CPS ≥ 1. Participants 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 participants with a new diagnosis of metastatic SCCHN. Participants for whom newly obtained samples cannot be obtained (eg, inaccessible or participant safety concern) 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. Collection of the tissue samples for PD-L1 assessments for Part 2B can be discontinued by the sponsor if sufficient data has been collected or dazostinag activity does not justify further collection.
   * For Part 2B, participants must be eligible to receive treatment with either cisplatin or carboplatin in combination with 5-fluorouracil (5-FU) 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 anti-PD-1 or PD-L1 antibody (i.e., 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 (i.e., cetuximab or bevacizumab). MSI-H/dMMR CRC participants must have received at least 6 weeks of prior treatment with an anti-PD-(L)-1 antibody. Only one line of anti-PD-(L)-1 is permitted.
   * 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 (i.e., 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 documented MSI/MMR status assessed by a Clinical Laboratory Improvements Amendment-certified (United States \[US\] sites or an accredited (outside of the US) local laboratory using immunohistochemistry (IHC) and/or polymerase chain reaction (PCR) or next generation sequencing (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.
   * 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, except for alopecia, Grade 2 peripheral neuropathy, and/or autoimmune endocrinopathies with stable endocrine replacement therapy.
9. 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/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 dazostinag treatment.
10. Must have at least 1 RECIST version 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. 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 one used for PK/pharmacodynamic collection.

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 0 Day 1 (C0D1) \[for Japan safety lead-in only\] and Cycle 1 Day 1 (C1D1) predose assessment.
3. Oxygen saturation less than (\<) 92 percent (%) on room air at screening or during C0D1 (for Japan safety lead-in only) and C1D1 predose assessment.
4. Treated with other STING agonists/antagonist and toll-like receptors agonists within the past 6 months.
5. 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.
6. History of brain and leptomeningeal metastasis unless:

   * Brain metastases are clinically and radiologically stable or improved (that is, ≥ 4 weeks) following surgery, whole-brain radiation, or stereotactic radiosurgery, AND
   * Off corticosteroids.
7. Ongoing Grade ≥ 2 infection or participants with Grade ≥ 2 fever of malignant origin.
8. Chronic, active hepatitis (example: participants with known hepatitis B surface antigen seropositive and/or detectable hepatitis C virus \[HCV\]- ribonucleic acid \[RNA\]).
9. For participants in the dose escalation SA Part 1A only: refusal of standard therapeutic options.
10. For participants receiving pembrolizumab only: contraindication and/or intolerance to the administration of pembrolizumab.
11. 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.
12. Participant 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.
13. 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.
14. 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.
15. 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 non-systemic corticosteroids.
    * Premedications required for computed tomography (CT) or magnetic resonance imaging (MRI) scans.
    * 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.
16. 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).
17. 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).
18. Recipients of allogeneic or autologous stem cell transplantation or organ transplantation.

    For Part 2 SCCHN only:
19. Has progressive disease within 6 months of completion of curatively intended systemic treatment for locoregionally advanced SCCHN.
20. 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.
21. Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2 or anti-cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) agent.
22. Participants with known dihydropyrimidine dehydrogenase (DPD) deficiency or thymidine phosphorylase gene (TYMP) mutations (Part 2B only).

Primary outcomes:
measure: Number of Participants Reporting one or More Treatment-emergent Adverse Events (TEAEs) and Based on TEAEs Severity
timeFrame: Up to approximately 68 months
measure: Number of Participants with Dose-Limiting Toxicities (DLTs)
timeFrame: Up to approximately 68 months
measure: Number of Participants Reporting One or More Treatment Emergent Serious Adverse Event (SAEs)
timeFrame: Up to approximately 68 months
measure: Number of Participants With one or More TEAEs Leading to Dose Modifications and Treatment Discontinuations
timeFrame: Up to approximately 68 months
Secondary outcomes:
measure: Dose Escalation, Japan Safety Lead-in, and Expansion Phases: Overall Response Rate (ORR)
timeFrame: Up to approximately 68 months
measure: Dose Escalation, Japan Safety Lead-in, and Expansion Phases: Disease Control Rate (DCR)
timeFrame: Up to approximately 68 months
measure: Dose Escalation, Japan Safety Lead-in, and Expansion Phases: Duration of Response (DOR)
timeFrame: Up to approximately 68 months
measure: Dose Escalation, Japan Safety Lead-in, and Expansion Phases: Time to Response (TTR)
timeFrame: Up to approximately 68 months
measure: Expansion Phase Only: Progression-Free Survival (PFS)
timeFrame: Up to approximately 29 months
measure: Expansion Phase Only: Overall Survival (OS)
timeFrame: Up to approximately 29 months
measure: Expansion Phase Only: OS Rate at 12 Months
timeFrame: Up to 29 months
measure: Expansion Phase Only: OS Rate at 6 Months
timeFrame: Up to 29 months
Other outcomes:
Locations:
city: La Jolla
country: United States
facility: University of California San Diego Moores Cancer Center
state: California
city: Los Angeles
country: United States
facility: Norris Comprehensive Cancer Center
state: California
city: Orange
country: United States
facility: UCI Health - Chao Family Comprehensive Cancer Center
state: California
city: Santa Monica
country: United States
facility: University of California Los Angeles - Jonsson Comprehensive Cancer Center
state: California
city: Denver
country: United States
facility: SCRI - HealthOne Denver
state: Colorado
city: New Haven
country: United States
facility: Yale Cancer Center
state: Connecticut
city: Gainesville
country: United States
facility: Memorial Cancer Institute at Memorial Hospital West - Cancer Institute/Radiology Oncology
state: Florida
city: Chicago
country: United States
facility: Robert H. Lurie Comprehensive Cancer Center of Northwestern University
state: Illinois
city: Baltimore
country: United States
facility: University of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer Center
state: Maryland
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Boston
country: United States
facility: Dana-Farber Cancer Institute
state: Massachusetts
city: Detroit
country: United States
facility: Barbara Ann Karmanos Cancer Institute - Lawrence and Idell Weisberg Cancer Treatment Center
state: Michigan
city: Creve Coeur
country: United States
facility: Siteman Cancer Center - West County
state: Missouri
city: Florissant
country: United States
facility: Siteman Cancer Center - North County
state: Missouri
city: Saint Louis
country: United States
facility: Washington University School of Medicine Siteman Cancer Center
state: Missouri
city: Saint Louis
country: United States
facility: Siteman Cancer Center - South County
state: Missouri
city: Saint Peters
country: United States
facility: Siteman Cancer Center - St. Peters
state: Missouri
city: Cincinnati
country: United States
facility: University of Cincinnati Health Barrett Cancer Center
state: Ohio
city: Cincinnati
country: United States
facility: University of Cincinnati Health Barrett Cancer Center
state: Ohio
city: West Chester
country: United States
facility: West Chester Hospital
state: Ohio
city: Portland
country: United States
facility: Providence Portland Medical Center
state: Oregon
city: Philadelphia
country: United States
facility: Fox Chase Cancer Center
state: Pennsylvania
city: Pittsburgh
country: United States
facility: University of Pittsburgh Medical Center (UPMC) Hillman Cancer Center
state: Pennsylvania
city: Nashville
country: United States
facility: Sarah Cannon Research Institute (SCRI)
state: Tennessee
city: Dallas
country: United States
facility: Mary Crowley Cancer Research
state: Texas
city: Fairfax
country: United States
facility: Virginia Cancer Specialists, P.C. - Fairfax
state: Virginia
city: Wels
country: Austria
facility: Klinikum Wels-Grieskirchen
state: Oberoesterreich
city: Toronto
country: Canada
facility: Princess Margaret Cancer Centre
state: Ontario
city: Montreal
country: Canada
facility: Jewish General Hospital
state: Quebec
city: Montreal
country: Canada
facility: McGill University Health Centre
state: Quebec
city: Beijing
country: China
facility: Beijing Cancer Hospital
state: Beijing Sheng
city: Guangzhou
country: China
facility: Sixth Affiliated Hospital of Sun Yat-Sen University/Guangdong Gastrointestinal Hospital
state: Guangzhou Sheng
city: Shanghai
country: China
facility: Fudan University Shanghai Cancer Center
state: Shanghai
city: Shanghai
country: China
facility: Shanghai East Hospital
state: Shanghai
city: Chengdu
country: China
facility: West China School of Medicine - West China Hospital of Sichuan University
state: Sichuan Sheng
city: Chengdu
country: China
facility: West China Hospital
state: Sichuan
city: Hangzhou
country: China
facility: Zhejiang Cancer Hospital
state: Zhejiang
city: Suresnes
country: France
facility: Hopital Foch
state: Ile-de-France
city: Besancon
country: France
facility: Centre Hospitalier Regional et Universitaire de Besancon - Hopital Jean-Minjoz
city: Bordeaux
country: France
facility: Hopital Saint-Andre
city: Dijon
country: France
facility: Centre Georges Francois Leclerc
city: Lille
country: France
facility: Centre de Lutte contre le Cancer - Centre Oscar Lambret
city: Lyon
country: France
facility: Centre Leon Berard
city: Marseille
country: France
facility: Hopital de la Timone
city: Paris
country: France
facility: Hopital Saint-Antoine
city: St Herblain
country: France
facility: Institut de Cancerologie de lOuest - Saint-Herblain - Site Rene Gauducheau
city: Villejuif
country: France
facility: Gustave Roussy
city: Beer Sheva
country: Israel
facility: Soroka Medical Center
city: Jerusalem
country: Israel
facility: Hadassah University Hospital Ein Kerem
city: Tel Aviv-Yafo
country: Israel
facility: Tel Aviv Sourasky Medical Center
city: Tel Hashomer
country: Israel
facility: The Chaim Sheba Medical Center
city: Chuo-Ku
country: Japan
facility: National Cancer Center Hospital
state: Tokyo
city: Warsaw
country: Poland
facility: Narodowy Instytut Onkologii im. Marii Sklodowskiej-Curie - Panstwowy Instytut Badawczy
state: Mazowieckie
city: San Juan
country: Puerto Rico
facility: PanOncology Trials: Universidad de Puerto Rico - Centro Comprensivo de Cancer
city: St. Gallen
country: Switzerland
facility: Kantonsspital Sankt Gallen
state: Saint Gallen
city: Bern
country: Switzerland
facility: Inselspital Universitatsspital Bern
city: Geneve
country: Switzerland
facility: Hopitaux Universitaires de Geneve
city: Lausanne
country: Switzerland
facility: Centre Hospitalier Universitaire Vaudois Lausanne
city: Belfast
country: United Kingdom
facility: Queen's University Belfast
state: Northern Ireland
city: Leeds
country: United Kingdom
facility: Leeds Teaching Hospitals NHS Trust
city: London
country: United Kingdom
facility: University College London Hospitals NHS Foundation Trust
city: Oxford
country: United Kingdom
facility: Oxford University Hospitals NHS Foundation Trust
Study officials:
affiliation: Takeda
name: Study Director
role: STUDY_DIRECTOR
References: