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Metastatic Thyroid Gland CarcinomaPhase 2NCT04731740

Pembrolizumab and Lenvatinib/Chemotherapy for Poorly Differentiated/Anaplastic Thyroid Cancer

A Phase 2 study testing Lenvatinib, Pembrolizumab and Chemotherapy in people with Metastatic Thyroid Gland Carcinoma and Poorly Differentiated Thyroid Gland Carcinoma, run by Saint Petersburg State University, Russia at 1 site in Russia.

Withdrawn

Withdrawn. The study stopped before anyone enrolled.

Official record
Search all trials

Trial summary

The aim of the study is to evaluate the efficacy of the combination of lenvatinib with pembrolizumab, and to establish a safe and effective systemic treatment regimen for patients with metastatic anaplastic thyroid cancer (ATC) / poorly differentiated thyroid cancer (PDTC). Read more about this study

Who is it for?
Ages 18 years and older
What is being tested?
Lenvatinib, Pembrolizumab and Chemotherapy
Type of treatment
Injection or infusion
Could I receive a placebo?
No, everyone receives an active treatment
How many people
0 participants
Where
1 siteRussia
Study dates
28 Dec 2020to 28 Dec 2023
Phase
Phase 2
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Male or female subjects ≥ 18 years of age.
  • Willingness to participate in the research by signing an informed consent form approved by the research ethics committee.
  • ECOG status 0 or 1 or 2.
  • Measurable disease according to RECIST 1.1, as defined by the investigator.
  • Patients with a histologically confirmed disease (according to the pathologist's report) that meets one of the following criteria (according to the 2010 WHO classification):
  • Poorly differentiated iodine-refractory thyroid tumors in the first line or after switching to chemotherapy or investigational drugs or anaplastic thyroid cancer in the first line or after switching to chemotherapy or investigational drugs. The primary tumor may or may not be removed, but the risk of aerodigestive compression or bleeding should be excluded.
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  • Radioactive iodine resistant disease (RAI), which is defined by one or more of the following criteria:
  • One or more measurable lesions that do not show RAI uptake.
  • One or more measurable lesions progressing on RECIST 1.1 = <14 months prior RAI therapy
  • One or more measurable lesions are present after a cumulative dose of RAI> = 600 mCi
  • One or more measurable lesions that are F-18 fludeoxyglucose (FDG) -avid (> 5 standardized absorbance value [SUV]) if positron emission tomography (PET) / CT is performed; these lesions can also be RAI-active
  • Patients with inoperable locally advanced disease or metastases. Patients who do not want to undergo surgery or radiation are also eligible. Patients with the BRAFV600E mutation who are unable to take FDA-approved drugs, dabrafenib / trametinib, or established progression with therapy are eligible for study treatment if documented.
  • Ability to collect samples, including blood and tumors, for translational studies.
  • Weight over 30 kg.
  • Recovery from toxicity associated with any prior treatment to grade ≤ 1, unless adverse events (AEs) are clinically significant and / or are stable with maintenance therapy.
  • Ability to swallow pills or have a gastrostomy.
  • Normal organ and bone marrow function as defined below (obtained = <30 days prior to study entry):
  • Hemoglobin ≥ 9.0 g / dL.
  • Absolute neutrophil count (ANC)> 1500 per mm.
  • Platelet count ≥ 100,000 per mm.
  • Serum bilirubin ≤ 1.5 times the upper limit of normal (ULN) if liver metastases are absent, in which case it should be ≤ 2X ULN. This does not apply to patients with confirmed Gilbert's syndrome (persistent or recurrent hyperbilirubinemia, which is predominantly unconjugated in the absence of hemolysis or liver pathology); however, they will only be admitted after consulting their doctor.
  • Aspartate transaminase (AST) (SGOT) / alanine aminotransferase (ALT) (SGPT) ≤ 2.5x the institutional upper limit of normal, unless liver metastases are present, in which case it should be ≤ 3x ULN.
  • Measured creatinine clearance (CL)> 40 ml / min or Estimated creatinine clearance> 40 ml / min using the Cockcroft-Gault formula (Cockcroft and Gault, 1976) or 24-hour urine collection to determine creatinine clearance.
  • Albumin> = 2.5 mg / dL (received = <30 days prior to registration)
  • International normalized ratio (INR) or prothrombin time (PT) = <1.5 X ULN if the subject is not receiving anticoagulant therapy while PT or partial thromboplastin time (PTT) is within the therapeutic range of the intended use of anticoagulants
  • Activated partial thromboplastin time (APTT) = <1.5 x ULN if the subject is not receiving anticoagulant therapy while the PT or PTT is within the therapeutic range of the intended use of anticoagulants
  • Adequately controlled blood pressure with or without antihypertensive drugs, defined as blood pressure (BP) <150/90 mm Hg.
  • Female subjects of childbearing age (not surgically sterile or at least 2 years of age in postmenopausal women) must present a negative pregnancy test at screening and use a medically accepted double-barrier method of contraception (e.g. spermicide condom + IUD or cervical caps). In addition, they must agree to continue using this double-barrier method for the duration of the study and for 4 months after the end of study participation. Women will be considered postmenopausal if they have had amenorrhea within 12 months without an alternative medical cause. The following age requirements apply:
  • Women under 50 are considered to be posttmenopausal if they have had amenorrhea for 12 months or more after stopping treatment with exogenous hormones, and if they have postmenpausal levels of luteinizing hormone and follicle-stimulating hormone or have undergone surgical sterilization (bilateral oophorectomy or hysterectomy)
  • Women over 50 years of age will be considered postmenopausal if they have had amenorrhea for 12 months or more after stopping all exogenous hormonal drugs with the last menstrual period> 1 year ago, had a menopause caused by chemotherapy with the last menstrual period> 1 year ago, or underwent surgery sterilization (bilateral oophorectomy, bilateral salpingectomy or hysterectomy).
  • Men must agree to abstain from intercourse with a female partner or agree to use a double-barrier method of contraception (for example, a spermicide condom, in addition to the fact that their female partner is using some form of contraception, such as an intrauterine device (IUD) or cervical caps), at the time of the study and for 4 months after the end of participation in the study.
  • Patient willingness and ability to adhere to protocol throughout the study, including undergoing treatment, and availability for scheduled visits and examinations, including follow-up.

Who cannot join

  • The presence of a confirmed BRAF mutation.
  • Concurrent participation in another clinical trial if it is not an observational (non-interventional) clinical trial or during the follow-up period of an interventional trial
  • Pretreatment with any immune checkpoint inhibitor therapy (eg anti-CTLA4, -PD-1 or -PD-L1).
  • Taking any type of low molecular weight kinase inhibitors (including the investigational kinase inhibitor) for 2 weeks or 5 half-lives of the agent, whichever is greater.
  • Receiving any type of anti-tumor antibodies (including test antibodies) or systemic chemotherapy within 2 weeks before starting treatment.
  • Current or previous use of immunosuppressants within 2 weeks prior to the first dose of study drugs, with the exception of intranasal and inhaled corticosteroids or systemic corticosteroids at physiological doses that should not exceed 10 mg / day of prednisone or an equivalent corticosteroid.
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  • Active or previously documented autoimmune disease within the past 2 years. Note: Patients with vitiligo, Graves' disease or psoriasis who do not require systemic treatment (within the last 2 years) are not excluded.
  • Active or previously documented inflammatory bowel disease (eg Crohn's disease and ulcerative colitis).
  • History of allogeneic organ transplantation.
  • Subjects diagnosed with immunodeficiency or receiving systemic steroid therapy or any other form of immunosuppressive therapy within 28 days prior to the first dose of study treatment.
  • Received radiation therapy for bone metastases within 2 weeks or any other radiation therapy within 4 weeks prior to enrollment. Subjects with clinically significant ongoing complications from previous radiation therapy that have not completely resolved are not eligible for the study (eg, radiation esophagitis or other internal inflammation).
  • Presence of metastases in the brain or epidural disease of the skull without adequate treatment with radiation therapy and / or surgery (including radiosurgery). Eligible patients should be neurologically asymptomatic and not receive corticosteroid medications during investigational treatment.
  • Concomitant therapy with oral anticoagulants (eg warfarin, direct thrombin and factor Xa inhibitors) or platelet inhibitors (eg clopidogrel), with the exception of the following approved anticoagulants:
  • Low-dose aspirin for cardioprotection (in accordance with current local guidelines) and low-dose low molecular weight heparins (LMWH).
  • Anticoagulant therapy with therapeutic doses of LMWH in subjects without known brain metastases who received a dose of LMWH for at least 6 weeks prior to enrollment and who had no clinically significant hemorrhagic complications from the anticoagulation regimen or tumor.
  • Subject has an uncontrolled, serious underlying medical condition or recent illness, including but not limited to the following conditions:
  • Cardiovascular diseases:
  • Congestive heart failure, grade 3 or 4 as defined by the New York Heart Association, unstable angina, and severe cardiac arrhythmias.
  • Uncontrolled hypertension, defined as sustained blood pressure> 150 mm Hg. Systolic or diastolic> 100 mmHg
  • Stroke, including transient ischemic attack (TIA), myocardial infarction, other ischemic events or thromboembolic event, such as deep vein thrombosis (DVT) and pulmonary embolism) within 6 months prior to inclusion. Subjects with a later diagnosis of DVT are eligible if they are stable, asymptomatic, and have received LMWH for at least 6 weeks prior to study treatment.
  • Gastrointestinal disorders (eg malabsorption syndrome or obstruction of the gastric outlet), including those associated with a high risk of perforation or fistula formation:
  • Active peptic ulcer disease, inflammatory bowel disease, ulcerative colitis, diverticulitis, cholecystitis, symptomatic cholangitis or appendicitis, acute pancreatitis or acute obstruction of the pancreas or bile ducts, or obstruction of the gastric outlet.
  • Abdominal fistula, gastrointestinal perforation, bowel obstruction, or intra-abdominal abscess within 6 months prior to inclusion. Note: Complete healing of the intra-abdominal abscess must be confirmed before starting treatment.
  • Clinically significant vomiting or hemoptysis> 0.5 teaspoon (> 2.5 ml) of red blood or other significant bleeding in history within 3 months prior to treatment.
  • Interstitial lung lesions or known manifestations of endobronchial disease. F) Lesions invading the main pulmonary blood vessels.
  • Other clinically significant disorders such as:
  • An active infection requiring systemic treatment, infection with human immunodeficiency virus or disease associated with acquired immunodeficiency syndrome, or chronic infection with hepatitis B or C.
  • Serious non-healing wound / ulcer / bone fracture.
  • Moderate or severe liver failure (Child-Pugh B or C).
  • The need for hemodialysis or peritoneal dialysis.
  • Uncontrolled diabetes mellitus.
  • History of solid organ transplantation.
  • Major surgery (such as gastrointestinal surgery and removal or biopsy of brain metastases) within 8 weeks prior to inclusion. Complete wound healing from major surgery should occur 4 weeks before the study treatment, and after minor surgery (eg, simple excision, tooth extraction) at least 10 days before the study treatment. Patients with clinically significant ongoing complications from prior surgery are not eligible.
  • Adjusted QT interval calculated by Fridericia formula (QTcf)> 500 ms for 28 days prior to study treatment.
  • Note: If a single ECG displays a QTCf with an absolute value> 500 ms, two additional ECGs at approximately 3 min intervals must be performed within 30 minutes of the initial ECG, and the average of these three consecutive results will be used to assess eligibility for study participation.
  • Pregnant (test must be done no later than 7 days before the start of the study) or lactating mothers.
  • Received any live vaccine = <30 days prior to study initiation.
  • Inability to swallow pills and lack of gastrostomy.
  • Previously identified allergy or hypersensitivity to the components of the investigational dosage forms.
  • Diagnosis of other malignant neoplasm within 3 years prior to study treatment, with the exception of superficial skin cancer or localized low-grade tumors that are considered cured and untreated by systemic therapy.
  • ADDITIONAL EXCLUSION CRITERION FOR COHORT 1 (pembrolizumab + lenvatinib): The presence of invasion (germination) of the tumor into the major great vessels or the presence of clinically significant blood clots in the arteries or veins.

Trial locations and contacts

1 site in 1 country.

Russia1 site

  • Saint-Petersburg State University (SPSU) N.I.Pirogov Clinic of High Medical Technologies

    Saint Petersburg

Other trials in Russia

About this study

Official title: Pembrolizumab in Combination With Standard 1st Line Therapy (Lenvatinib / Chemotherapy) for Locally Advanced or Metastatic Poorly Differentiated or Anaplastic Thyroid Cancer

The aim of the study is to evaluate the efficacy of the combination of lenvatinib with pembrolizumab, and to establish a safe and effective systemic treatment regimen for patients with metastatic anaplastic thyroid cancer (ATC) / poorly differentiated thyroid cancer (PDTC).

Lenvatinib is an anti-angiogenic and antiproliferative drug used in differentiated thyroid cancer. It blocks proliferative genes such as RET and PDGFR and further inhibits major proliferation pathways such as VEGF receptor signaling and FGFR1-4.

Pembrolizumab is an immune checkpoint inhibitor that targets PD-1 located on lymphocytes. The response to pembrolizumab treatment is associated, among other things, with increased expression of PD-L1, as well as with the frequency of somatic mutations in the respective tumors. Patients with ATC / PDTC show high expression of PD-L1.

Read the detailed description

Primary endpoint

  1. Objective Response Ratio (ORR) [Time frame: prior to study completion, average 3 years]
  • Evaluate the effectiveness of a combination of a PD-1 inhibitor (pembrolizumab) with a multikinase inhibitor (lenvatinib) using an objective response rate (ORR) in poorly differentiated or anaplastic thyroid cancer at 12 weeks and 24 weeks after starting treatment.
  • Evaluate the efficacy of the investigator's choice of chemotherapy plus PD-1 inhibitor (pembrolizumab) using an objective response rate (ORR) in poorly differentiated or anaplastic thyroid cancer at 12 weeks and 24 weeks after initiation of treatment. Includes patients with a confirmed partial (PR) and complete response (CR) as the best response according to RECIST v 1.1.
  1. Overall survival at 6 months in the pembrolizumab and lenvatinib cohort [Time frame: 6 months]

Secondary endpoints

  1. Safety Profile (Number / Severity of Serious Adverse Events, SAEs) [Timeline: SAEs will be reported in the clinical trial within 6 months of the end of the study]
  2. Duration of Response (DoR) [Time frame: from date of first documented clinical response (PR, CR) to date of first documented progression, date of death from any cause or patient failure, whichever comes first, is estimated to be 36 months]
  3. Progression-Free Survival (PFS) [Time frame: from date of enrollment to date of first documented progression, date of death from any cause or patient failure, whichever is earlier, up to 36 months]
  4. Overall Survival (OS) [Time frame: from the date of enrollment to the date of death from any cause or patient failure, whichever comes first, estimated up to 36 months]

Study design Prospective interventional two-cohort non-comparative single-center study.

Being tested
Lenvatinib, Pembrolizumab, Chemotherapy
Medical subject headings
Thyroid Neoplasms

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • LenvatinibDrug

    Also called E7080, ER-203492-00

    PO

  • PembrolizumabBiological

    Also called Keytruda, MK-3475, Lambrolizumab, SCH 900475

    IV

  • ChemotherapyDrug

    Investigators' choice

Study groups in NCT04731740
Study groupRoleWhat they receive
Pembrolizumab + LenvatinibExperimentalExperimental treatment: Lenvatinib p.o. once a day, pembrolizumab 200 mg i.v. every 21 days started 21 days after start of Lenvatinib Duration of treatment per patient: until the end of month 36 after registration of the last patient or disease progression or toxicity (whichever occurs first)
Receives: Drug: Lenvatinib; Biological: Pembrolizumab
Pembrolizumab + ChemotherapyExperimentalExperimental treatment: Investigators' choice of the Сhemotherapy, pembrolizumab 200 mg i.v. every 21 days started 21 days after the start of chemotherapy Duration of treatment per patient: until the end of month 36 after registration of the last patient or disease progression or toxicity (whichever occurs first)
Receives: Biological: Pembrolizumab; Drug: Chemotherapy

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Overall response rate (ORR)

    ORR will be calculated as the number of patients with an observed response divided by the number of patients included in the study. A two-sided confidence interval will be calculated at 80% (in accordance with the specified α) and 95% (for comparison with the literature).

    Measured: prior to study completion, average 3 years

  2. Overall survival at 6 months in cohort Lenvatinib+Pembrolizumab

    Overall survival is defined as the time from the date of initiation of treatment to death from any cause that will be assessed using the Kaplan-Meier method.

    Measured: 6 months

Secondary outcomes (4)

  1. Safety Profile (Number / Severity of Serious Adverse Events, SAEs)

    Number of serious adverse events classified by severity as assessed by CTCAE v4.0

    Measured: SAEs will be reported in the clinical trial within 6 months of the end of the study

  2. Duration of Response (DoR)

    Time from the date of the first documented CR or PR to the first documented progression or death due to cancer. DoR will be determined based on tumor score (RECIST criteria version 1.1).

    Measured: from date of first documented clinical response (PR, CR) to date of first documented progression, date of death from any cause or patient failure, whichever comes first, is estimated to be 36 months

  3. Progression-Free Survival (PFS)

    Median progression-free survival (mPFS) is defined as the time from the date of inclusion to the date of the first documented progression of disease or death from any cause, whichever occurs first. PFS will be determined based on the tumor score (RECIST criteria version 1.1).

    Measured: from date of enrollment to date of first documented progression, date of death from any cause or patient failure, whichever is earlier, up to 36 months

  4. Overall Survival (OS)

    Mean overall survival (mOS) is calculated as the time from the date of inclusion to the date of death for any reason.

    Measured: from the date of enrollment to the date of death from any cause or patient failure, whichever comes first, estimated up to 36 months

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted1 Feb 2021
  2. Study start28 Dec 2020
  3. Primary completion28 Dec 2023
  4. Study completion28 Dec 2023

Why it stopped: Lack of funding

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Non-randomised
Intervention model
Parallel groups
Model description
Two parallel arms based on the inclusion/exclusion criteria: Pembrolizumab+Lenvatinib or Pembrolizumab+Chemotherapy
Masking
None (open label)
Enrolment
0 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT04731740
Sponsor's protocol ID
73
Status last verified
Mar 2024
First submitted
26 Jan 2021
Last updated
25 Mar 2024
Results posted
No
Data monitoring committee
No
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
No

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Lenvatinib, Pembrolizumab and Chemotherapy in people with Metastatic Thyroid Gland Carcinoma and Poorly Differentiated Thyroid Gland Carcinoma, run by Saint Petersburg State University, Russia at 1 site in Russia.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 32 inclusion and 41 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: withdrawn, as of the sponsor's last update on 25 Mar 2024. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in Russia. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study was withdrawn before enrolling participants, so there are no results.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Overall response rate (ORR) (time frame: prior to study completion, average 3 years). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT04731740.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 25 Mar 2024.

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