Clinical trial NCT04381650: A Study of TAK-981 Given With Pembrolizumab in Participants With Select Advanced or Metastatic Solid Tumors
Official title: A Phase 1b/2 Study of TAK-981 Plus Pembrolizumab to Evaluate the Safety, Tolerability, and Antitumor Activity of the Combination in Patients With Select Advanced or Metastatic Solid Tumors
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Advanced or Metastatic Solid Tumors
Keywords: Drug Therapy
Lead sponsor: Takeda
Sponsor class: INDUSTRY
Collaborators: name: Takeda Development Center Americas, Inc.
First posted: 2020-05-11
Enrollment: 109
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Intervention model description: This study has 2 Phases. Phase 1 is dose escalation phase with sequential drug assignment. Phase 2 is parallel assignment.
Primary purpose: TREATMENT

Brief summary: TAK-981 is being tested in combination with pembrolizumab to treat participants who have select advanced or metastatic solid tumors.

The study aims are to evaluate the safety, tolerability, and preliminary efficacy of TAK-981 in combination with pembrolizumab.

Participants will be on this combination treatment for 21-day cycles. They will continue with this treatment for up to 24 months or until participants meet any discontinuation criteria.

Detailed description: The drug being tested in this study is called TAK-981. TAK-981 is being tested to treat people who have select advanced or metastatic solid tumors. The study will include a dose escalation phase and a dose expansion phase.

The study will enroll approximately 231 participants, approximately 32 participants in the dose escalation phase 1 and approximately 76 to 199 participants in the 8 cohorts of dose expansion phase 2. Participants will receive escalating doses of TAK-981 and fixed dose of pembrolizumab until recommended phase 2 dose (RP2D) is determined:

• Dose Escalation: TAK-981 + Pembrolizumab (Fixed Dose)

Once Phase 2 doses are identified, participants of select advanced or metastatic solid tumors will receive TAK-981 in below defined cohorts in the expansion phase 2:

* Dose Expansion Phase: Cohort A: Non-squamous Non-small Cell Lung Cancer (NSCLC)
* Dose Expansion Phase: Cohort B: Cervical Cancer
* Dose Expansion Phase: Cohort C: Microsatellite Stable Colorectal Cancer (MSS-CRC)
* Dose Expansion Phase: Cohort D: Cutaneous Melanoma
* Dose Expansion Phase: Cohort E: Squamous NSCLC
* Dose Expansion Phase: Cohort F: Checkpoint Inhibitors (CPI) Refractory Squamous or Nonsquamous NSCLC

This multi-center trial will be conducted worldwide. The overall time to participate in this study is 60 months. Participants will make multiple visits to the clinic, and progression-free survival follow-up for maximum up to 12 months after last dose of study drug.

Eligibility criteria: Inclusion Criteria:

1. Has a histologically or cytologically documented, advanced (metastatic and/or unresectable) cancer as listed below that is incurable: Note: Prior neoadjuvant or adjuvant therapy included in initial treatment may not be considered first- or later-line standard of care treatment unless such treatments were completed less than 12 months prior to the current tumor recurrence.

   A. Non-squamous NSCLC for which prior standard first-line treatment containing an anti-programmed cell death protein 1/programmed cell death protein 1 ligand (PD-1/PD-L1) checkpoint inhibitor (CPI) alone or in combination has failed and that has progressed on no more than 1 prior systemic therapy. In Phase 2, participants with nonsquamous NSCLC must have not received more than 1 prior systemic therapy and must not have presented with disease progression during the first 6 months of treatment with first-line CPI/anti-PD-(1/L1)-containing therapy.

   Note: In Phase 1, participants with nonsquamous NSCLC and known driver mutations/genomic aberrations (e.g., epidermal growth factor receptor (EGFR), B-Raf proto-oncogene mutation V600E \[BRAF V600E\], and ROS proto-oncogene 1 \[ROS1\] sensitizing mutations, neurotrophic receptor tyrosine kinase \[NRTK\] gene fusions, and anaplastic lymphoma kinase \[ALK\] rearrangements) must have also shown progressive disease after treatment with a commercially available targeted therapy. In Phase 2, participants with driver mutations are not eligible.

   B. CPI-naive cervical cancer (squamous cell carcinoma, adenosquamous carcinoma or adenocarcinoma of the cervix) participants for whom prior standard first-line treatment has failed and who have received no more than 1 prior systemic line of therapy for recurrent or Stage IVB cervical cancer. Note: The following cervical tumors are not eligible: minimal deviation/adenoma malignum, gastric-type adenocarcinoma, clear-cell carcinoma, and mesonephric carcinoma. Histologic confirmation of the original primary tumor is required via pathology report. Note: First-line treatment must have consisted of platinum-containing doublet. Chemotherapy administered concurrently with primary radiation (e.g., weekly cisplatin) is not counted as a systemic chemotherapy regimen.

   C. CPI-naïve microsatellite stable-colorectal cancer (MSS-CRC) participants for whom prior standard first-line treatment has failed and who have progressed on no more than 3 chemotherapy regimens.

   Note: Participants must have received prior treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-containing regimens if indicated.

   D. Unresectable Stage III or Stage IV cutaneous melanoma that has not received prior therapy in the metastatic setting.

   Note: Participants with acral melanoma are not eligible. Participants who have presented with disease relapse after ≥6 months of the last dose of CPI or BRAF-mitogen-activated protein kinase kinase (MEK) inhibitor in the adjuvant setting are eligible.

   E. Squamous NSCLC for which prior standard first-line treatment containing an anti-PD-(1/L1) checkpoint inhibitor alone or in combination has failed. Participant must have not received more than 1 prior systemic therapy and must not have presented with disease progression during the first 6 months of treatment with first-line CPI/anti-PD-(1/L1)-containing therapy.

   F. Squamous or nonsquamous NSCLC for which prior standard first-line treatment containing an anti-PD-(1/L1) checkpoint inhibitor alone or in combination has failed within 6 months from the initiation of the CPI. Participants must not have received more than 1 prior systemic therapy in the metastatic setting.

   Note: Participants with driver mutations are not eligible.
2. Has at least 1 radiologically measurable lesion based on RECIST, Version 1.1. Tumor lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions.
3. Has a performance status of 0 or 1 on the Eastern Cooperative Group Oncology (ECOG) Performance Scale.
4. Has left ventricular ejection fraction (LVEF) ≥40%; as measured by echocardiogram (ECHO) or multiple-gated acquisition (MUGA) scan.
5. Has recovered to Grade 1 or baseline from all toxicity associated with previous therapy or have the toxicity established as sequela. Note: Has a neuropathy ≤Grade 2, any grade alopecia, or autoimmune endocrinopathies with stable replacement therapy are permitted.
6. Demonstrate adequate organ function as described below:

A. Platelet count ≥75.0 × 10\^9/L. B. Absolute neutrophil count (ANC) ≥1.0 × 10\^9/L. C. Hemoglobin ≥85 g/L (red blood cell \[RBC\] transfusion allowed ≥14 days before assessment).

D. Calculated creatinine clearance ≥30 mL/min using the Cockcroft-Gault formula.

E. Aspartate aminotransferase (AST, GOT) and alanine aminotransferase (ALT, GPT) ≤3.0 times the upper limit of normal (ULN), \<5.0 times the ULN if liver enzyme elevations are due to liver metastases; bilirubin ≤1.5 times the ULN. Participants with Gilbert's syndrome may have a bilirubin level \>1.5 times the ULN, per discussion between the investigator and the medical monitor.

Exclusion Criteria:

1. History of uncontrolled brain metastasis (evidence of progression by imaging over a period of 4 weeks and/or neurologic symptoms that have not returned to baseline). Participant with treated brain metastases are allowed provided they are radiologically stable, without evidence of progression for at least 4 weeks by repeat imaging, clinically stable, and without requirement of steroid treatment for at least 14 days prior to first dose of study treatment. Note: For asymptomatic participants, screening brain imaging is not required.
2. Second malignancy within the previous 3 years, except treated basal cell or localized squamous skin carcinomas, localized prostate cancer, cervical carcinoma in situ, resected colorectal adenomatous polyps, breast cancer in situ, or other malignancy for which the participant is not on active anticancer therapy.
3. Major surgery ≤14 days from the first dose of study drug and not recovered fully from any complications from surgery.
4. History of immune-related AEs related to treatment with immune CPIs that required treatment discontinuation.
5. Receiving or requires the continued use of medications that are known to be strong or moderate inhibitors and inducers of cytochrome P-450 (CYP) 3A4/5 and strong P-glycoprotein (Pgp) inhibitors.
6. Baseline prolongation of the QT interval corrected using Fridericia's formula (QTcF) (e.g., repeated demonstration of QTcF interval \>480 milliseconds (ms), history of congenital long QT syndrome, or torsades de pointes).
7. Has a history of autoimmune disease requiring systemic immunosuppressive therapy with daily doses of prednisone \>10 mg/day or equivalent doses, or any other form of immunosuppressive therapy. Hormone replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for thyroid, adrenal or pituitary insufficiency) for endocrinopathies are not considered prohibited forms of systemic treatment of an autoimmune disease.
8. Has a history of noninfectious pneumonitis that required steroids or a history of interstitial lung disease.
9. Has an evidence of active, non-infectious pneumonitis.
10. Has a history of allogeneic tissue or solid organ transplant.
11. Has an active infection requiring systemic therapy.
12. Has a known history of human immunodeficiency virus (HIV) infection or any other relevant congenital or acquired immunodeficiency.
13. Has a known hepatitis B virus surface antigen seropositive or detectable hepatitis C infection viral load. Note: Participants who have positive hepatitis B core antibody or hepatitis B surface antigen antibody can be enrolled but must have an undetectable hepatitis B viral load.
14. History of any of the following ≤6 months before first dose: congestive heart failure New York Heart Association Grade III or IV, unstable angina, myocardial infarction, unstable symptomatic ischemic heart disease, uncontrolled hypertension despite appropriate medical therapy, ongoing symptomatic cardiac arrhythmias \>Grade 2, pulmonary embolism or symptomatic cerebrovascular events, or any other serious cardiac condition (e.g., pericardial effusion or restrictive cardiomyopathy). Chronic atrial fibrillation on stable anticoagulant therapy is allowed.
15. Psychiatric illness/social circumstances that would limit compliance with study requirements and substantially increase the risk of AEs or has compromised ability to provide written informed consent.

Primary outcomes:
measure: Phase 1: Number of Participants With One or More Treatment Emergent Adverse Events (TEAEs)
timeFrame: Up to 48 months
measure: Phase 1: Number of Participants With Dose Limiting Toxicities (DLTs)
timeFrame: Up to Cycle 1 (each cycle is of 21 days)
measure: Phase 1: Number of Participants With Grade 3 or Higher Treatment Emergent Adverse Events (TEAEs)
timeFrame: Up to 48 months
measure: Phase 1: Number of Participants With One or More Serious Adverse Events (SAEs)
timeFrame: Up to 48 months
measure: Phase 1: Number of Participants with One or More TEAEs Leading to Dose Modifications and Treatment Discontinuation
timeFrame: Up to 48 months
measure: Phase 1: Number of Participants With Clinically Significant Laboratory Values
timeFrame: Up to 48 months
measure: Phase 2: Overall Response Rate (ORR) as Assessed by the Investigator According to RECIST, Version 1.1
timeFrame: Up to 60 months
Secondary outcomes:
measure: Phase 1: Cmax: Maximum Observed Plasma Concentration for TAK-981
timeFrame: Cycle 1 (each cycle is 21 days) Days 1 and 8 pre-dose and at multiple timepoints (Up to 24 hours); Days 4 and 11: at the end of infusion; Cycle 2, Days 1 and 8, at the end of infusion and at 2 hours post-dose
measure: Phase 1: Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for TAK-981
timeFrame: Cycle 1 (each cycle is 21 days) Days 1 and 8 pre-dose and at multiple timepoints (Up to 24 hours); Days 4 and 11: at the end of infusion; Cycle 2, Days 1 and 8, at the end of infusion and at 2 hours post-dose
measure: Phase 1: AUCt: Area Under the Plasma Concentration-time Curve from Time 0 to Time t Over the Dosing Interval for TAK-981
timeFrame: Cycle 1 (each cycle is 21 days) Days 1 and 8 pre-dose and at multiple timepoints (Up to 24 hours); Days 4 and 11: at the end of infusion; Cycle 2, Days 1 and 8, at the end of infusion and at 2 hours post-dose
measure: Phase 1: AUC∞: Area Under the Plasma Concentration-time Curve from Time 0 to Infinity for TAK-981
timeFrame: Cycle 1 (each cycle is 21 days) Days 1 and 8 pre-dose and at multiple timepoints (Up to 24 hours); Days 4 and 11: at the end of infusion; Cycle 2, Days 1 and 8, at the end of infusion and at 2 hours post-dose
measure: Phase 1: t1/2z: Terminal Disposition Phase Half-life for TAK-981
timeFrame: Cycle 1 (each cycle is 21 days) Days 1 and 8 pre-dose and at multiple timepoints (Up to 24 hours); Days 4 and 11: at the end of infusion; Cycle 2, Days 1 and 8, at the end of infusion and at 2 hours post-dose
measure: Phase 1: CL: Total Clearance After Intravenous Administration for TAK-981
timeFrame: Cycle 1 (each cycle is 21 days) Days 1 and 8 pre-dose and at multiple timepoints (Up to 24 hours); Days 4 and 11: at the end of infusion; Cycle 2, Days 1 and 8, at the end of infusion and at 2 hours post-dose
measure: Phase 1: Vss: Volume of Distribution at Steady State After Intravenous Administration for TAK-981
timeFrame: Cycle 1 (each cycle is 21 days) Days 1 and 8 pre-dose and at multiple timepoints (Up to 24 hours); Days 4 and 11: at the end of infusion; Cycle 2, Days 1 and 8, at the end of infusion and at 2 hours post-dose
measure: Phases 1 and 2: ORR as Defined by the Investigator According to Modified RECIST, Version 1.1 for Immune-Based Therapeutics (iRECIST) Modification
timeFrame: Up to 60 months
measure: Phases 1 and 2: Disease Control Rate (DCR)
timeFrame: Up to 60 months
measure: Phases 1 and 2: Durable Response Rate (DRR)
timeFrame: Up to 60 months
measure: Phases 1 and 2: Duration of Response (DOR)
timeFrame: Up to 60 months
measure: Phases 1 and 2: Progression-free Survival (PFS)
timeFrame: Up to 60 months
measure: Phases 1 and 2: Time to Response (TTR)
timeFrame: Up to 60 months
measure: Phases 1 and 2: Time to Progression (TTP)
timeFrame: Up to 60 months
measure: Phase 2: Overall Survival (OS)
timeFrame: Up to 60 months
measure: Phase 1: Percentage of Participants at Each Dose Level Demonstrating Adduct Formation in Blood
timeFrame: Up to 48 months
measure: Phase 1: Percent Change in Small Ubiquitin-like Modifier (SUMO) 2/3 Signal With Pre and Post-dose in Blood
timeFrame: Up to 48 months
measure: Phase 2: Percentage of Participants With One or More Treatment Emergent Adverse Events (TEAEs)
timeFrame: Up to 60 months
measure: Phase 2: Number of Participants With Grade 3 or Higher Treatment Emergent Adverse Events (TEAEs)
timeFrame: Up to 60 months
measure: Phase 2: Number of Participants with One or More TEAEs Leading to Dose Modifications and Treatment Discontinuation
timeFrame: Up to 60 months
Other outcomes:
Locations:
city: Scottsdale
country: United States
facility: HonorHealth
state: Arizona
city: Orange
country: United States
facility: University of California Irvine Medical Center
state: California
city: Stanford
country: United States
facility: Stanford Cancer Institute (SCI)
state: California
city: New Haven
country: United States
facility: Yale Cancer Center
state: Connecticut
city: Augusta
country: United States
facility: Georgia Cancer Center at Augusta University
state: Georgia
city: Bethesda
country: United States
facility: The Center for Cancer and Blood Disorders - PPDS
state: Maryland
city: Morristown
country: United States
facility: Morristown Medical Center
state: New Jersey
city: New Brunswick
country: United States
facility: Cancer Institute of New Jersey
state: New Jersey
city: Bronx
country: United States
facility: Montefiore Einstein Cancer Center - BRANY - PPDS
state: New York
city: Chapel Hill
country: United States
facility: University of North Carolina at Chapel Hill
state: North Carolina
city: Oklahoma City
country: United States
facility: University of Oklahoma Peggy and Charles Stephenson Cancer Center
state: Oklahoma
city: Portland
country: United States
facility: Providence Cancer Institute, Franz Clinic
state: Oregon
city: Philadelphia
country: United States
facility: Fox Chase Cancer Center
state: Pennsylvania
city: Pittsburgh
country: United States
facility: UPMC Hillman Cancer Center
state: Pennsylvania
city: Dallas
country: United States
facility: University of Texas Southwestern Medical Center
state: Texas
city: San Antonio
country: United States
facility: START South Texas Accelerated Research Therapeutics
state: Texas
city: Charlottesville
country: United States
facility: University of Virginia Health System
state: Virginia
city: Fairfax
country: United States
facility: Virginia Cancer Specialists (Fairfax) - USOR
state: Virginia
city: Curitiba
country: Brazil
facility: Instituto de Oncologia Do Parana
state: Parana
city: Ijui
country: Brazil
facility: ONCOSITE Centro de Pesquisa Clinica Em Oncologia
state: Rio Grande Do Sul
city: Porto Alegre
country: Brazil
facility: Hospital de Clinicas de Porto Alegre (HCPA) - PPDS
state: Rio Grande Do Sul
city: Porto Alegre
country: Brazil
facility: Hospital Sao Lucas Da Pontificia Universidade Catolica Do Rio Grande Do Sul (PUCRS)
state: Rio Grande Do Sul
city: Barretos
country: Brazil
facility: Fundacao Pio XII Hospital de Cancer de Barretos
state: Sao Paulo
city: Sao Jose Do Rio Preto
country: Brazil
facility: Hospital de Base Da Faculdade de Medicina de Sao Jose Do Rio Preto
state: Sao Paulo
city: Belo Horizonte
country: Brazil
facility: Cetus Hospital Dia Oncologia
city: Rio De Janeiro
country: Brazil
facility: INCA Instituto Nacional de Cancer
city: Rio de Janeiro
country: Brazil
facility: Instituto Do Cancer Do Estado de Sao Paulo Octavio Frias de Oliveira
city: Guangzhou
country: China
facility: Sun Yat-Sen University Cancer Center
state: Guangdong
city: Wuhan
country: China
facility: Union Hospital Tongji Medical College Huazhong University of Science and Technology
state: Hubei
city: Hangzhou
country: China
facility: The First Affiliated Hospital, Zhejiang University School of Medicine - PPDS
state: Zhejiang
city: Zagreb
country: Croatia
facility: Klinicki bolnicki centar Zagreb
state: Grad Zagreb
city: Osijek
country: Croatia
facility: Clinical Hospital Centre Osijek
city: Pula
country: Croatia
facility: General Hospital Pula
city: Split
country: Croatia
facility: University Hospital Centre Split
city: Kashiwa-Shi
country: Japan
facility: National Cancer Center East
state: Tiba
city: Chuo-Ku
country: Japan
facility: National Cancer Center Hospital
state: Tokyo
city: Chuo-Ku
country: Japan
facility: The Cancer Institute Hospital of Japanese Foundation For Cancer Research
state: Tokyo
city: Riga
country: Latvia
facility: Pauls Stradins Clinical University Hospital
city: Riga
country: Latvia
facility: Riga East Clinical University Hospital Latvian Oncology Center
city: Kaunas
country: Lithuania
facility: Hospital of Lithuanian University of Health Sciences Kaunas Clinics
state: Kauno Apskritis
city: Kaunas
country: Lithuania
facility: Hospital of Lithuanian University of Health Sciences Kauno klinikos
state: Kauno Apskritis
city: Vilnius
country: Lithuania
facility: National Cancer Institute
state: Vilniaus Apskritis
city: Lodz
country: Poland
facility: Centrum Terapii Wspolczesnej
state: Lodzkie
city: Gdansk
country: Poland
facility: Uniwersyteckie Centrum Kliniczne-Ul. Smoluchowskiego 17
state: Pomorskie
city: Bydgoszcz
country: Poland
facility: Centrum Onkologii im. Prof. Franciszka Lukaszczyka w Bydgoszczy
city: Lodz
country: Poland
facility: Instytut Medyczny Santa Familia Sp. z o. o.
city: Lublin
country: Poland
facility: Specjalistyczna Praktyka Lekarska Slawomir Mandziuk
city: Olsztyn
country: Poland
facility: Warminsko-Mazurskie Centrum Chorob Pluc w Olsztynie
city: Poznan
country: Poland
facility: Med-Polonia Sp. z o.o.
city: Munsterlingen
country: Switzerland
facility: Kantonsspital Muensterlingen
state: Thurgau (de)
city: Winterthur
country: Switzerland
facility: Kantonsspital Winterthur
state: Zurich (de)
city: Bern
country: Switzerland
facility: Universitaetsspital Bern - Inselspital
Study officials:
affiliation: Takeda
name: Study Director
role: STUDY_DIRECTOR
References:
citation: Nakamura A, Grossman S, Song K, Xega K, Zhang Y, Cvet D, Berger A, Shapiro G, Huszar D. The SUMOylation inhibitor subasumstat potentiates rituximab activity by IFN1-dependent macrophage and NK cell stimulation. Blood. 2022 May 5;139(18):2770-2781. doi: 10.1182/blood.2021014267.