A Study of TAK-981 Given With Pembrolizumab in Participants With Select Advanced or Metastatic Solid Tumors

Phase 1

Active, not recruiting

• Conditions: Advanced or Metastatic Solid Tumors
• Interventions: Drug: TAK-981; Drug: Pembrolizumab

• Registration Number: NCT04381650
• Lead Sponsor: Takeda

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.

Study Timeline

• Study First Submitted: 2020-05-06
• Study First Submitted QC: 2020-05-06
• Study First Posted: 2020-05-11
• Study Start: 2020-08-17
• Status Verified: 2024-03
• Last Update Submitted: 2024-03-21
• Last Update Posted: 2024-03-22
• Primary Completion: 2025-11-30
• Study Completion: 2025-11-30

Recruitment & Eligibility

• Status: ACTIVE_NOT_RECRUITING
• Sex: All
• Target Recruitment: 49

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.

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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.

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Dose Expansion Phase: Cohort C: MSS-CRC	TAK-981	TAK-981 as IV infusion in participants with microsatellite stable colorectal cancer (MSS-CRC) on Days 1, 4, 8 and 11 or Days 1 and 8 or Days 1, 8 and 15 in each 21-day Treatment Cycle up to disease progression or 24-months and pembrolizumab 200 mg IV infusion as a fixed dose every 3 weeks on Day 1 of 21-day Treatment Cycle for a maximum of 24 months.
Dose Escalation: TAK-981 + Pembrolizumab (Fixed Dose)	TAK-981	Escalating doses of TAK-981 with starting dose of 40 mg, intravenous (IV) infusion, on Days 1, 4, 8 and 11 or Days 1 and 8 or Days 1, 8 and 15 in each 21-day Treatment Cycle and pembrolizumab 200 mg, IV infusion, as a fixed dose every 3 weeks on Day 1 of 21-day Treatment Cycle until RP2D is determined (for a maximum of 24 months).
Dose Expansion Phase: Cohort B: Cervical Cancer	TAK-981	TAK-981 as IV infusion in participants with cervical cancer on Days 1, 4, 8 and 11 or Days 1 and 8 or Days 1, 8 and 15 in each 21-day Treatment Cycle up to disease progression or 24-months and pembrolizumab 200 mg IV infusion as a fixed dose every 3 weeks on Day 1 of 21-day Treatment Cycle for a maximum of 24 months.
Dose Expansion Phase: Cohort A: Non-squamous NSCLC	TAK-981	TAK-981 as IV infusion in participants with non-squamous non-small cell lung cancer (NSCLC) on Days 1, 4, 8 and 11 or Days 1 and 8 or Days 1, 8 and 15 in each 21-day Treatment Cycle up to disease progression or 24-months and pembrolizumab 200 mg IV infusion as a fixed dose every 3 weeks on Day 1 of 21-day Treatment Cycle for a maximum of 24 months.
Dose Expansion Phase: Cohort D: Cutaneous Melanoma	TAK-981	TAK-981 as IV infusion in participants with cutaneous melanoma on Days 1, 4, 8 and 11 or Days 1 and 8 or Days 1, 8 and 15 in each 21-day Treatment Cycle up to disease progression or 24-months and pembrolizumab 200 mg IV infusion as a fixed dose every 3 weeks on Day 1 of 21-day Treatment Cycle for a maximum of 24 months.
Dose Expansion Phase: Cohort F: CPI Refractory Squamous or Nonsquamous NSCLC	TAK-981	TAK-981 as IV infusion in participants with checkpoint inhibitors (CPI) refractory squamous or nonsquamous NSCLC on Days 1, 4, 8 and 11 or Days 1 and 8 or Days 1, 8 and 15 in each 21-day Treatment Cycle up to disease progression or 24-months and pembrolizumab 200 mg IV infusion as a fixed dose every 3 weeks on Day 1 of 21-day Treatment Cycle for a maximum of 24 months.
Dose Expansion Phase: Cohort E: Squamous NSCLC	TAK-981	TAK-981 as IV infusion in participants with squamous non-small cell lung cancer (NSCLC) on Days 1, 4, 8 and 11 or Days 1 and 8 or Days 1, 8 and 15 in each 21-day Treatment Cycle up to disease progression or 24-months and pembrolizumab 200 mg IV infusion as a fixed dose every 3 weeks on Day 1 of 21-day Treatment Cycle for a maximum of 24 months.
Dose Escalation: TAK-981 + Pembrolizumab (Fixed Dose)	Pembrolizumab	Escalating doses of TAK-981 with starting dose of 40 mg, intravenous (IV) infusion, on Days 1, 4, 8 and 11 or Days 1 and 8 or Days 1, 8 and 15 in each 21-day Treatment Cycle and pembrolizumab 200 mg, IV infusion, as a fixed dose every 3 weeks on Day 1 of 21-day Treatment Cycle until RP2D is determined (for a maximum of 24 months).
Dose Expansion Phase: Cohort A: Non-squamous NSCLC	Pembrolizumab	TAK-981 as IV infusion in participants with non-squamous non-small cell lung cancer (NSCLC) on Days 1, 4, 8 and 11 or Days 1 and 8 or Days 1, 8 and 15 in each 21-day Treatment Cycle up to disease progression or 24-months and pembrolizumab 200 mg IV infusion as a fixed dose every 3 weeks on Day 1 of 21-day Treatment Cycle for a maximum of 24 months.
Dose Expansion Phase: Cohort B: Cervical Cancer	Pembrolizumab	TAK-981 as IV infusion in participants with cervical cancer on Days 1, 4, 8 and 11 or Days 1 and 8 or Days 1, 8 and 15 in each 21-day Treatment Cycle up to disease progression or 24-months and pembrolizumab 200 mg IV infusion as a fixed dose every 3 weeks on Day 1 of 21-day Treatment Cycle for a maximum of 24 months.
Dose Expansion Phase: Cohort C: MSS-CRC	Pembrolizumab	TAK-981 as IV infusion in participants with microsatellite stable colorectal cancer (MSS-CRC) on Days 1, 4, 8 and 11 or Days 1 and 8 or Days 1, 8 and 15 in each 21-day Treatment Cycle up to disease progression or 24-months and pembrolizumab 200 mg IV infusion as a fixed dose every 3 weeks on Day 1 of 21-day Treatment Cycle for a maximum of 24 months.
Dose Expansion Phase: Cohort D: Cutaneous Melanoma	Pembrolizumab	TAK-981 as IV infusion in participants with cutaneous melanoma on Days 1, 4, 8 and 11 or Days 1 and 8 or Days 1, 8 and 15 in each 21-day Treatment Cycle up to disease progression or 24-months and pembrolizumab 200 mg IV infusion as a fixed dose every 3 weeks on Day 1 of 21-day Treatment Cycle for a maximum of 24 months.
Dose Expansion Phase: Cohort E: Squamous NSCLC	Pembrolizumab	TAK-981 as IV infusion in participants with squamous non-small cell lung cancer (NSCLC) on Days 1, 4, 8 and 11 or Days 1 and 8 or Days 1, 8 and 15 in each 21-day Treatment Cycle up to disease progression or 24-months and pembrolizumab 200 mg IV infusion as a fixed dose every 3 weeks on Day 1 of 21-day Treatment Cycle for a maximum of 24 months.
Dose Expansion Phase: Cohort F: CPI Refractory Squamous or Nonsquamous NSCLC	Pembrolizumab	TAK-981 as IV infusion in participants with checkpoint inhibitors (CPI) refractory squamous or nonsquamous NSCLC on Days 1, 4, 8 and 11 or Days 1 and 8 or Days 1, 8 and 15 in each 21-day Treatment Cycle up to disease progression or 24-months and pembrolizumab 200 mg IV infusion as a fixed dose every 3 weeks on Day 1 of 21-day Treatment Cycle for a maximum of 24 months.

Primary Outcome Measures

Name	Time	Method
Phase 1: Number of Participants With Dose Limiting Toxicities (DLTs)	Up to Cycle 1 (each cycle is of 21 days)	DLTs will be evaluated according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), Version 5.0 except cytokine release syndrome (CRS), will be graded according to American society for transplantation and cellular therapy (ASCST) Consensus Grading for CRS.
Phase 1: Number of Participants With Grade 3 or Higher Treatment Emergent Adverse Events (TEAEs)	Up to 48 months
Phase 1: Number of Participants With Clinically Significant Laboratory Values	Up to 48 months	Laboratory parameters includes parameters of clinical chemistry, hematology, and urinalysis.
Phase 1: Number of Participants With One or More Treatment Emergent Adverse Events (TEAEs)	Up to 48 months	An adverse event (AE) is any untoward medical occurrence in a participant administered a medicinal investigational drug. The untoward medical occurrence does not necessarily have to have a causal relationship with treatment. A TEAE is defined as an AE that occurs after administration of first dose of study drug and through 30 days after last dose of study drug or until start of subsequent antineoplastic therapy. AEs will be evaluated according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), Version 5.0 except cytokine release syndrome (CRS), will be graded according to American society for transplantation and cellular therapy (ASCST) Consensus Grading for CRS.
Phase 1: Number of Participants With One or More Serious Adverse Events (SAEs)	Up to 48 months	An SAE is any untoward medical occurrence that results in death; is life-threatening; requires inpatient hospitalization or prolongation of present hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect or is a medically important event that may not be immediately life-threatening or result in death or hospitalization, but may jeopardize the participant or may require intervention to prevent one of other outcomes listed in definition above, or involves suspected transmission via a medicinal product of an infectious agent.
Phase 1: Number of Participants with One or More TEAEs Leading to Dose Modifications and Treatment Discontinuation	Up to 48 months
Phase 2: Overall Response Rate (ORR) as Assessed by the Investigator According to RECIST, Version 1.1	Up to 60 months	ORR is defined as the percentage of participants who achieve Complete Response (CR) and Partial Response (PR) (determined by the investigator) during the study according to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1.

Secondary Outcome Measures

Name	Time	Method
Phase 1: AUCt: Area Under the Plasma Concentration-time Curve from Time 0 to Time t Over the Dosing Interval for TAK-981	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
Phase 1: t1/2z: Terminal Disposition Phase Half-life for TAK-981	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
Phase 1: CL: Total Clearance After Intravenous Administration for TAK-981	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
Phase 1: Cmax: Maximum Observed Plasma Concentration for TAK-981	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
Phases 1 and 2: ORR as Defined by the Investigator According to Modified RECIST, Version 1.1 for Immune-Based Therapeutics (iRECIST) Modification	Up to 60 months
Phases 1 and 2: Disease Control Rate (DCR)	Up to 60 months	DCR is defined as the percentage of participants who achieve stable disease (SD) or better (CR+PR+SD determined by the investigator) during the study.
Phases 1 and 2: Durable Response Rate (DRR)	Up to 60 months	DRR is defined as the rate of objective responses (CR + PR) maintained for at least 6 months initiating at any time within 12 months of commencing therapy.
Phases 1 and 2: Duration of Response (DOR)	Up to 60 months	DOR is defined as a time from the time of first documentation of tumor response to the first recorded occurrence of disease progression (PD) or death from any cause (whichever occurs first), through end of study (up to approximately 60 months).
Phases 1 and 2: Time to Progression (TTP)	Up to 60 months	TTP is defined as the from the date of the first dose administration to the date of the first documentation of PD as defined by standard disease criteria.
Phase 1: Percentage of Participants at Each Dose Level Demonstrating Adduct Formation in Blood	Up to 48 months	TAK-981-small ubiquitin-like modifier (SUMO) adduct formation in blood will be evaluated.
Phase 2: Number of Participants With Grade 3 or Higher Treatment Emergent Adverse Events (TEAEs)	Up to 60 months
Phase 1: Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for TAK-981	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
Phases 1 and 2: Time to Response (TTR)	Up to 60 months	TTR is defined as time from the date of the first dose administration to the date of first documented PR or better (up to approximately 60 months).
Phase 1: Vss: Volume of Distribution at Steady State After Intravenous Administration for TAK-981	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
Phases 1 and 2: Progression-free Survival (PFS)	Up to 60 months	PFS is defined as time from the date of the first dose administration to the date of first documentation of PD or death due to any cause whichever occurs first, through the end of the study (up to approximately 60 months).
Phase 1: AUC∞: Area Under the Plasma Concentration-time Curve from Time 0 to Infinity for TAK-981	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
Phase 1: Percent Change in Small Ubiquitin-like Modifier (SUMO) 2/3 Signal With Pre and Post-dose in Blood	Up to 48 months	SUMO pathway inhibition in blood will be evaluated.
Phase 2: Number of Participants with One or More TEAEs Leading to Dose Modifications and Treatment Discontinuation	Up to 60 months
Phase 2: Overall Survival (OS)	Up to 60 months	OS is defined as the time from the date of the first dose administration to the date of death. Participants without documentation of death at the time of analysis will be censored at the date last known to be alive.
Phase 2: Percentage of Participants With One or More Treatment Emergent Adverse Events (TEAEs)	Up to 60 months

Trial Locations

Locations (52)

Fox Chase Cancer Center; 🇺🇸 Philadelphia, Pennsylvania, United States

Cancer Institute of New Jersey; 🇺🇸 New Brunswick, New Jersey, United States

University of California Irvine Medical Center; 🇺🇸 Orange, California, United States

Stanford Cancer Institute (SCI); 🇺🇸 Stanford, California, United States

Georgia Cancer Center at Augusta University; 🇺🇸 Augusta, Georgia, United States

Hospital Sao Lucas Da Pontificia Universidade Catolica Do Rio Grande Do Sul (PUCRS); 🇧🇷 Porto Alegre, Rio Grande Do Sul, Brazil

HonorHealth; 🇺🇸 Scottsdale, Arizona, United States

Uniwersyteckie Centrum Kliniczne-Ul. Smoluchowskiego 17; 🇵🇱 Gdansk, Pomorskie, Poland

Instytut Medyczny Santa Familia Sp. z o. o.; 🇵🇱 Lodz, Poland

National Cancer Institute; 🇱🇹 Vilnius, Vilniaus Apskritis, Lithuania

Centrum Onkologii im. Prof. Franciszka Lukaszczyka w Bydgoszczy; 🇵🇱 Bydgoszcz, Poland

National Cancer Center Hospital; 🇯🇵 Chuo-Ku, Tokyo, Japan

Riga East Clinical University Hospital Latvian Oncology Center; 🇱🇻 Riga, Latvia

Kantonsspital Winterthur; 🇨🇭 Winterthur, Zurich (de), Switzerland

START South Texas Accelerated Research Therapeutics; 🇺🇸 San Antonio, Texas, United States

University of Oklahoma Peggy and Charles Stephenson Cancer Center; 🇺🇸 Oklahoma City, Oklahoma, United States

Providence Cancer Institute, Franz Clinic; 🇺🇸 Portland, Oregon, United States

Morristown Medical Center; 🇺🇸 Morristown, New Jersey, United States

Montefiore Einstein Cancer Center - BRANY - PPDS; 🇺🇸 Bronx, New York, United States

University of North Carolina at Chapel Hill; 🇺🇸 Chapel Hill, North Carolina, United States

UPMC Hillman Cancer Center; 🇺🇸 Pittsburgh, Pennsylvania, United States

University of Texas Southwestern Medical Center; 🇺🇸 Dallas, Texas, United States

Virginia Cancer Specialists (Fairfax) - USOR; 🇺🇸 Fairfax, Virginia, United States

Instituto de Oncologia Do Parana; 🇧🇷 Curitiba, Parana, Brazil

ONCOSITE Centro de Pesquisa Clinica Em Oncologia; 🇧🇷 Ijui, Rio Grande Do Sul, Brazil

Hospital de Clinicas de Porto Alegre (HCPA) - PPDS; 🇧🇷 Porto Alegre, Rio Grande Do Sul, Brazil

Fundacao Pio XII Hospital de Cancer de Barretos; 🇧🇷 Barretos, Sao Paulo, Brazil

Hospital de Base Da Faculdade de Medicina de Sao Jose Do Rio Preto; 🇧🇷 Sao Jose Do Rio Preto, Sao Paulo, Brazil

Cetus Hospital Dia Oncologia; 🇧🇷 Belo Horizonte, Brazil

INCA Instituto Nacional de Cancer; 🇧🇷 Rio De Janeiro, Brazil

Sun Yat-Sen University Cancer Center; 🇨🇳 Guangzhou, Guangdong, China

Instituto Do Cancer Do Estado de Sao Paulo Octavio Frias de Oliveira; 🇧🇷 Rio de Janeiro, Brazil

Union Hospital Tongji Medical College Huazhong University of Science and Technology; 🇨🇳 Wuhan, Hubei, China

The First Affiliated Hospital, Zhejiang University School of Medicine - PPDS; 🇨🇳 Hangzhou, Zhejiang, China

Clinical Hospital Centre Osijek; 🇭🇷 Osijek, Croatia

Klinicki bolnicki centar Zagreb; 🇭🇷 Zagreb, Grad Zagreb, Croatia

General Hospital Pula; 🇭🇷 Pula, Croatia

National Cancer Center East; 🇯🇵 Kashiwa-Shi, Tiba, Japan

University Hospital Centre Split; 🇭🇷 Split, Croatia

The Cancer Institute Hospital of Japanese Foundation For Cancer Research; 🇯🇵 Chuo-Ku, Tokyo, Japan

Pauls Stradins Clinical University Hospital; 🇱🇻 Riga, Latvia

Hospital of Lithuanian University of Health Sciences Kaunas Clinics; 🇱🇹 Kaunas, Kauno Apskritis, Lithuania

Hospital of Lithuanian University of Health Sciences Kauno klinikos; 🇱🇹 Kaunas, Kauno Apskritis, Lithuania

Centrum Terapii Wspolczesnej; 🇵🇱 Lodz, Lodzkie, Poland

Specjalistyczna Praktyka Lekarska Slawomir Mandziuk; 🇵🇱 Lublin, Poland

Med-Polonia Sp. z o.o.; 🇵🇱 Poznan, Poland

Warminsko-Mazurskie Centrum Chorob Pluc w Olsztynie; 🇵🇱 Olsztyn, Poland

Kantonsspital Muensterlingen; 🇨🇭 Munsterlingen, Thurgau (de), Switzerland

Universitaetsspital Bern - Inselspital; 🇨🇭 Bern, Switzerland

Yale Cancer Center; 🇺🇸 New Haven, Connecticut, United States

The Center for Cancer and Blood Disorders - PPDS; 🇺🇸 Bethesda, Maryland, United States

University of Virginia Health System; 🇺🇸 Charlottesville, Virginia, United States