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JOURNAL ONKOLOGIE – STUDIE
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A Study of Dazostinag as Single Agent and Dazostinag in Combination With Pembrolizumab in Adults With Advanced or Metastatic Solid Tumors

Rekrutierend

NCT-Nummer:
NCT04420884

Studienbeginn:
Juli 2020

Letztes Update:
03.04.2024

Wirkstoff:
Pembrolizumab, Platinum, 5-Fluorouracil, Dazostinag

Geschlecht:
Alle

Altersgruppe:
Erwachsene (18+)

Phase:
-

Sponsor:
Takeda

Collaborator:
-

Studienleiter

Study Director
Study Director
Takeda

Kontakt

Studienlocations
(3 von 77)

UCI Health - Chao Family Comprehensive Cancer Center
92868 Orange
United StatesNoch nicht rekrutierend» Google-Maps
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Site Contact
Phone: 949-999-2400
E-Mail: rrbanker@hs.uci.edu» Ansprechpartner anzeigen
University of California Los Angeles - Jonsson Comprehensive Cancer Center
90404-2023 Santa Monica
United StatesRekrutierend» Google-Maps
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Site Contact
Phone: 310-586-2094
E-Mail: zwainberg@mednet.ucla.edu» Ansprechpartner anzeigen
Memorial Cancer Institute at Memorial Hospital West - Cancer Institute/Radiology Oncology
32610 Gainesville
United StatesNoch nicht rekrutierend» Google-Maps
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Site Contact
Phone: 352-265-0725
E-Mail: jc.fabregas@ufl.edu» Ansprechpartner anzeigen
Robert H. Lurie Comprehensive Cancer Center of Northwestern University
60611 Chicago
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Phone: 312-695-1300
E-Mail: jochen.lorch@nm.org» Ansprechpartner anzeigen
University of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer Center
21201-1544 Baltimore
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Site Contact
Phone: 410-328-7224
E-Mail: ranee.mehra@umm.edu» Ansprechpartner anzeigen
Barbara Ann Karmanos Cancer Institute - Lawrence and Idell Weisberg Cancer Treatment Center
48201-2013 Detroit
United StatesRekrutierend» Google-Maps
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Site Contact
Phone: 313-576-8778
E-Mail: sukaria@karmanos.org» Ansprechpartner anzeigen
Washington University School of Medicine Siteman Cancer Center
63110-1032 Saint Louis
United StatesRekrutierend» Google-Maps
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Site Contact
Phone: 314-747-8475
E-Mail: dadkins@dom.wustl.edu» Ansprechpartner anzeigen
University of Pittsburgh Medical Center (UPMC) Hillman Cancer Center
15232 Pittsburgh
United StatesRekrutierend» Google-Maps
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Site Contact
Phone: 773-702-6180
E-Mail: lukejj@upmc.edu» Ansprechpartner anzeigen
Landesklinikum Wiener Neustadt
2700 Wiener Neustadt
AustriaRekrutierend» Google-Maps
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Site Contact
Phone: +43 262 290 041 2801
E-Mail: birgit.gruenberger@wienerneustadt.lknoe.at» Ansprechpartner anzeigen
Universitair Ziekenhuis Leuven - Campus Gasthuisberg
3000 Leuven
BelgiumNoch nicht rekrutierend» Google-Maps
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Site Contact
Phone: +32 1 634 42 18
E-Mail: sabine.tejpar@uzleuven.be» Ansprechpartner anzeigen
Sixth Affiliated Hospital of Sun Yat-Sen University/Guangdong Gastrointestinal Hospital
510655 Guangzhou
ChinaNoch nicht rekrutierend» Google-Maps
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Site Contact
Phone: +86 20-38250745
E-Mail: dengyanh@mail.sysu.edu.cn» Ansprechpartner anzeigen
West China School of Medicine - West China Hospital of Sichuan University
610610 Chengdu
ChinaRekrutierend» Google-Maps
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Site Contact
Phone: +86 18980601776
E-Mail: qiumeng33@hotmail.com» Ansprechpartner anzeigen
Centre Hospitalier Regional et Universitaire de Besancon - Hopital Jean-Minjoz
25000 Besancon
FranceRekrutierend» Google-Maps
Ansprechpartner:
Site Contact
Phone: +33381668166;+33381479999
E-Mail: christophe.borg@efs.sante.fr» Ansprechpartner anzeigen
Institut de Cancerologie de lOuest - Saint-Herblain - Site Rene Gauducheau
44805 St Herblain
FranceRekrutierend» Google-Maps
Ansprechpartner:
Site Contact
Phone: +33 01-42-41-28-25
E-Mail: ludovic.doucet@ico.unicancer.fr» Ansprechpartner anzeigen
Narodowy Instytut Onkologii im. Marii Sklodowskiej-Curie - Panstwowy Instytut Badawczy
02-034 Warsaw
PolandRekrutierend» Google-Maps
Ansprechpartner:
Site Contact
Phone: +48 506159219; +480225462000
E-Mail: lucjanwyrwicz@gmail.com» Ansprechpartner anzeigen
PRCCI Site: Puerto Rico Medical Research Center Torre Medica Hospital Auxilio Mutuo
00917 San Juan
Puerto RicoNoch nicht rekrutierend» Google-Maps
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Site Contact
Phone: 787-900-5661; 787-296-8394
E-Mail: jlozada@prmedcenter.com» Ansprechpartner anzeigen
PanOncology Trials: Universidad de Puerto Rico - Centro Comprensivo de Cancer
00936 San Juan
Puerto RicoRekrutierend» Google-Maps
Ansprechpartner:
Site Contact
Phone: 787-407-3333
E-Mail: maria.garcia@panoncologytrials.com» Ansprechpartner anzeigen
The Royal Marsden NHS Foundation Trust
SM2 5NG Sutton
United KingdomRekrutierend» Google-Maps
Ansprechpartner:
Site Contact
Phone: +442086613158; +442073528171
E-Mail: david.cunningham@icr.ac.uk» Ansprechpartner anzeigen
University College London Hospitals NHS Foundation Trust
NW1 2BU London
United KingdomRekrutierend» Google-Maps
Ansprechpartner:
Site Contact
Phone: +442034477210; +44 2079357700
E-Mail: m.forster@ucl.ac.uk» Ansprechpartner anzeigen
The Royal Marsden NHS Foundation Trust
SW3 6JJ London
United KingdomRekrutierend» Google-Maps
Ansprechpartner:
Site Contact
Phone: +442086613158; +442073528171
E-Mail: david.cunningham@icr.ac.uk» Ansprechpartner anzeigen
The Christie NHS Foundation Trust
M20 4BX Manchester
United KingdomNoch nicht rekrutierend» Google-Maps
Ansprechpartner:
Site Contact
Phone: +441614463439; +441614463156
E-Mail: mark.saunders8@nhs.net» Ansprechpartner anzeigen
Oxford University Hospitals NHS Foundation Trust
Ox1 2JD Oxford
United KingdomRekrutierend» Google-Maps
Ansprechpartner:
Site Contact
Phone: +44 01865 617411
E-Mail: eileen.parkes@oncology.ox.ac.uk» Ansprechpartner anzeigen
Alle anzeigen

Studien-Informationen

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 368 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.

Additional dose levels of Dazostinag (such as 3.5 mg or 7.0 mg and higher) 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* *Dose

optimization will be performed in either Part 2A SCCHN or Part 3B CRC.

This multi-center trial will be conducted worldwide. The overall time to participate in this

study is 62.9 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.

Ein-/Ausschlusskriterien

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.

- 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 treatment initiation 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, 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 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. 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,

>=6 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]-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 (PD) 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 PD (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).

Studien-Rationale

Primary outcome:

1. Number of Participants Reporting one or More Treatment-emergent Adverse Events (TEAEs) and Based on TEAEs Severity (Time Frame - Up to approximately 54 months):
A severity grade is defined by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 5.0. Grade 1 scales as Mild (asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated); Grade 2 scales as Moderate (minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental Activities of Daily Living [ADL]); Grade 3 scales as Severe (severe or medically significant but not immediately life threatening hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care ADL); Grade 4 scales as Life-threatening consequences, urgent intervention indicated, and Grade 5 scales as Death related to Adverse Event (AE).

2. Number of Participants with Dose-Limiting Toxicities (DLTs) (Time Frame - Up to approximately 54 months):
A DLT will be defined as any of the TEAEs, but not limited to, those that occur during Cycle 1 and are considered by the investigator to be at least possibly related to dazostinag as a single agent (SA) or in combination with pembrolizumab. TEAEs meeting DLT definitions occurring in Cycle 2 or later will be considered in the determination of the RDE of dazostinag, both in the dazostinag SA and the combination with pembrolizumab arms. Toxicity will be evaluated according to NCI CTCAE version 5.0.

3. Number of Participants Reporting One or More Treatment Emergent Serious Adverse Event (SAEs) (Time Frame - Up to approximately 54 months)

4. Number of Participants With one or More TEAEs Leading to Dose Modifications and Treatment Discontinuations (Time Frame - Up to approximately 54 months)

Secondary outcome:

1. Dose Escalation, Japan Safety Lead-in, and Expansion Phases: Cmax: Maximum Observed Plasma Concentration for Dazostinag (Time Frame - Dose Escalation, Japan Safety Lead-in, and Expansion Phases: Cycle 1 Days 1, 8 and 15: pre-infusion and at multiple time points (up to 24 hours) post-infusion and at Day 1 for further cycles up to 54 months (Cycle length=21 days))

2. Dose Escalation, Japan Safety Lead-in, and Expansion Phases: Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Dazostinag (Time Frame - Dose Escalation, Japan Safety Lead-in, and Expansion Phases: Cycle 1 Days 1, 8 and 15: pre-infusion and at multiple time points (up to 24 hours) post-infusion and at Day 1 for further cycles up to 54 months (Cycle length=21 days))

3. Dose Escalation, Japan Safety Lead-in, and Expansion Phases: AUCt: Area Under the Concentration-time Curve From Time 0 to Time t for Dazostinag (Time Frame - Dose Escalation, Japan Safety Lead-in, and Expansion Phases: Cycle 1 Days 1, 8 and 15: pre-infusion and at multiple time points (up to 24 hours) post-infusion and at Day 1 for further cycles up to 54 months (Cycle length=21 days))

4. Dose Escalation, Japan Safety Lead-in, and Expansion Phases: AUCinf: Area Under the Concentration-time Curve From Time 0 to Infinity for Dazostinag (Time Frame - Dose Escalation, Japan Safety Lead-in, and Expansion Phases: Cycle 1 Days 1, 8 and 15: pre-infusion and at multiple time points (up to 24 hours) post-infusion and at Day 1 for further cycles up to 54 months (Cycle length=21 days))

5. Dose Escalation, Japan Safety Lead-in, and Expansion Phases: t1/2z: Terminal Disposition Phase Half-life for Dazostinag (Time Frame - Dose Escalation, Japan Safety Lead-in, and Expansion Phases: Cycle 1 Days 1, 8 and 15: pre-infusion and at multiple time points (up to 24 hours) post-infusion and at Day 1 for further cycles up to 54 months (Cycle length=21 days))

6. Dose Escalation, Japan Safety Lead-in, and Expansion Phases: CL: Total Clearance After Intravenous Administration for Dazostinag (Time Frame - Dose Escalation, Japan Safety Lead-in, and Expansion Phases: Cycle 1 Days 1, 8 and 15: pre-infusion and at multiple time points (up to 24 hours) post-infusion and at Day 1 for further cycles up to 54 months (Cycle length=21 days))

7. Dose Escalation, Japan Safety Lead-in, and Expansion Phases: Vss: Volume of Distribution at Steady State After Intravenous Administration for Dazostinag (Time Frame - Dose Escalation, Japan Safety Lead-in, and Expansion Phases: Cycle 1 Days 1, 8 and 15: pre-infusion and at multiple time points (up to 24 hours) post-infusion and at Day 1 for further cycles up to 54 months (Cycle length=21 days))

8. Dose Escalation, Japan Safety Lead-in, and Expansion Phases: CLR: Renal Clearance for Dazostinag (Time Frame - Dose Escalation, Japan Safety Lead-in, and Expansion Phases: Cycle 1 Days 1, 8 and 15: pre-infusion and at multiple time points (up to 24 hours) post-infusion and at Day 1 for further cycles up to 54 months (Cycle length=21 days))

9. Dose Escalation, Japan Safety Lead-in, and Expansion Phases: Percentage of Dose Excreted in Urine During 24 Hours After Dosing (Time Frame - Dose Escalation, Japan Safety Lead-in, and Expansion Phases: Cycle 1 Days 1, 8 and 15: pre-infusion and at multiple time points (up to 24 hours) post-infusion and at Day 1 for further cycles up to 54 months (Cycle length=21 days))

10. Dose Escalation, Japan Safety Lead-in, and Expansion Phases: CLR/CL%: Renal Clearance as Percentage of Total Clearance for Dazostinag (Time Frame - Dose Escalation, Japan Safety Lead-in, and Expansion Phases: Cycle 1 Days 1, 8 and 15: pre-infusion and at multiple time points (up to 24 hours) post-infusion and at Day 1 for further cycles up to 54 months (Cycle length=21 days))

11. Dose Escalation Phase: Percentage of Dose Excreted in Feces During 24 Hours After Dosing (Time Frame - Dose Escalation Phase: Cycle 1 Day 1: from start of infusion and at multiple time points (up to 24 hours) post-infusion (Cycle length=21 days))

12. Dose Escalation, Japan Safety Lead-in, and Expansion Phases: Overall Response Rate (ORR) (Time Frame - Up to approximately 54 months):
ORR is defined as the percentage of participants who achieve confirmed complete response (cCR) + confirmed partial response (cPR) during the study in response-evaluable population. ORR will be assessed based on Response Evaluation Criteria in Solid Tumor (RECIST) version 1.1.

13. Dose Escalation, Japan Safety Lead-in, and Expansion Phases: Disease Control Rate (DCR) (Time Frame - Up to approximately 54 months):
DCR is defined as the percentage of participants who achieve cCR + cPR + stable disease (SD) greater than (>) 6 weeks during the study in response-evaluable population. The DCR will be assessed based on RECIST version 1.1.

14. Dose Escalation, Japan Safety Lead-in, and Expansion Phases: Duration of Response (DOR) (Time Frame - Up to approximately 54 months):
DOR is the time from the date of first documentation of a cPR or better to the date of first documentation of progressive disease for responders (cPR or better). Responders without documentation of progressive disease will be censored at the date of last response assessment that is SD or better. DOR will be assessed based on RECIST version 1.1.

15. Dose Escalation, Japan Safety Lead-in, and Expansion Phases: Time to Response (TTR) (Time Frame - Up to approximately 54 months):
TTR is defined as the time from the date of first dose administration to the date of first documented cPR or better by the investigator. TTR will be assessed based on RECIST version 1.1.

16. Dose Escalation, Japan Safety Lead-in, and Expansion Phases: Fold Change from Baseline in Upregulation of Dazostinag-induced Stimulator of Interferon Genes (STING) (Time Frame - Baseline up to Month 54)

17. Dose Escalation, Japan Safety Lead-in, and Expansion Phases: Fold Change from Baseline in T-cell Infiltration Upon Dazostinag Treatment (Time Frame - Baseline up to Month 54)

18. Dose Escalation, Japan Safety Lead-in, and Expansion Phases: Fold Change from Baseline of Genomic, Transcriptomic and Protein Expressions in Tumor Tissues (Time Frame - Baseline up to Month 54)

19. Expansion Phase Only: Progression-Free Survival (PFS) (Time Frame - Up to approximately 24 months):
PFS is defined as the time from the date of first dose administration to the date of first documented disease progression or death due to any cause, whichever occurs first.

20. Expansion Phase Only: Overall Survival (OS) (Time Frame - Up to approximately 24 months):
OS is defined as the time from the date of first dose administration to the date of death.

21. Expansion Phase Only: OS Rate at 12 Months (Time Frame - Up to 24 months):
12-month OS rate is defined as the percentage of participants who are still alive at 12 months from their first dose administration.

22. Expansion Phase Only: OS Rate at 6 Months (Time Frame - Up to 24 months):
6-month OS rate is defined as the percentage of participants who are still alive at 6 months from their first dose administration.

Studien-Arme

  • Experimental: Part 1 (Monotherapy Dose Escalation Phase): Dazostinag Safety Lead-in + Dazostinag SA [Part 1A]
    Safety Lead-in: Dazostinag 0.1 mg, infusion, intravenously (IV), once weekly, on Days 1, 8 and 15 in 21-day treatment cycles. Dazostinag single agent (SA) Dose Escalation (Part 1A): Dazostinag 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.
  • Experimental: Part 1B (Combination Dose Escalation Phase): Dazostinag + Pembrolizumab
    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.
  • Experimental: Japan Safety Lead-in Dazostinag ± Pembrolizumab
    Dazostinag 5.0 mg, infusion, IV, once on Day 1 in Cycle 0 (cycle length=7 days) in Japanese participants with advanced or metastatic solid tumors. Following the 7-day Cycle 0, participants who do not develop any DLT in Cycle 0 will be administered Dazostinag on Days 1, 8, and 15 of a 21-day cycle in combination with pembrolizumab administered Q3W, IV, in Cycle 1. If no DLTs are observed, study treatment will start with Dazostinag in combination with pembrolizumab administered on Day 1 of each 21-day treatment cycle. Additional dose levels of Dazostinag (such as 3.5 mg or 7.0 mg and higher) in combination with pembrolizumab (200 mg, Q3W) may be explored in the Safety Lead in.
  • Experimental: Part 2A (SCCHN CPS ≥ 1 Dose Expansion and Optimization Phase): Dazostinag + Pembrolizumab
    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.
  • Experimental: Part 2B (SCCHN Dose Expansion Phase): Dazostinag + Pembrolizumab + Chemotherapy
    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 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) every 3 weeks for up to 6 cycles.
  • Experimental: Experimental: Part 3A (Expansion Phase in CRC): Dazostinag + Pembrolizumab in MSI-H/dMMR CRC
    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.
  • Experimental: Part 3B (Expansion and Dose Optimization Phase in CRC): Dazostinag + Pembrolizumab in MSS/pMMR CRC
    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. Dose optimization may be performed in this phase.

Geprüfte Regime

  • Dazostinag (TAK-676):
    Dazostinag intravenous Infusion.
  • Pembrolizumab:
    Pembrolizumab intravenous Infusion.
  • Platinum:
    Carboplatin or Cisplatin intravenous infusion
  • 5-fluorouracil:
    5-fluorouracil intravenous infusion

Quelle: ClinicalTrials.gov


Sie können folgenden Inhalt einem Kollegen empfehlen:

"A Study of Dazostinag as Single Agent and Dazostinag in Combination With Pembrolizumab in Adults With Advanced or Metastatic Solid Tumors"

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