Clinical Trials /

Atezolizumab With Chemotherapy in Treating Patients With Anaplastic or Poorly Differentiated Thyroid Cancer

NCT03181100

Description:

This phase II trial studies how well atezolizumab in combination with chemotherapy works in treating patients with anaplastic or poorly differentiated thyroid cancer. Immunotherapy with monoclonal antibodies, such as atezolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Vemurafenib and cobimetinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Monoclonal antibodies, such as bevacizumab, may interfere with the ability of cancer cells to grow and spread. Drugs such as nab-paclitaxel and paclitaxel work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. This trial is being done to see if atezolizumab in combination with chemotherapy works better in treating patients with anaplastic or poorly differentiated thyroid cancer compared to standard treatments.

Related Conditions:
  • Poorly Differentiated Thyroid Gland Carcinoma
  • Thyroid Gland Undifferentiated (Anaplastic) Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Atezolizumab With Chemotherapy in Treating Patients With Anaplastic or Poorly Differentiated Thyroid Cancer
  • Official Title: Atezolizumab Combinations With Chemotherapy for Anaplastic and Poorly Differentiated Thyroid Carcinomas

Clinical Trial IDs

  • ORG STUDY ID: 2016-0916
  • SECONDARY ID: NCI-2019-02581
  • SECONDARY ID: 2016-0916
  • SECONDARY ID: P30CA016672
  • NCT ID: NCT03181100

Conditions

  • Metastatic Thyroid Gland Carcinoma
  • Poorly Differentiated Thyroid Gland Carcinoma
  • Stage IVA Thyroid Gland Anaplastic Carcinoma AJCC v8
  • Stage IVB Thyroid Gland Anaplastic Carcinoma AJCC v8
  • Stage IVC Thyroid Gland Anaplastic Carcinoma AJCC v8
  • Thyroid Gland Anaplastic Carcinoma
  • Unresectable Thyroid Gland Carcinoma

Interventions

DrugSynonymsArms
AtezolizumabMPDL 3280A, MPDL 328OA, MPDL-3280A, MPDL3280A, MPDL328OA, RG7446, RO5541267, TecentriqCohort I (vemurafenib, cobimetinib, atezolizumab)
BevacizumabAnti-VEGF, Anti-VEGF Humanized Monoclonal Antibody, Anti-VEGF rhuMAb, Avastin, Bevacizumab Biosimilar BEVZ92, Bevacizumab Biosimilar BI 695502, Bevacizumab Biosimilar CBT 124, Bevacizumab Biosimilar FKB238, Bevacizumab Biosimilar MIL60, Bevacizumab Biosimilar QL 1101, BEVACIZUMAB, LICENSE HOLDER UNSPECIFIED, Immunoglobulin G1 (Human-Mouse Monoclonal rhuMab-VEGF Gamma-Chain Anti-Human Vascular Endothelial Growth Factor), Disulfide With Human-Mouse Monoclonal rhuMab-VEGF Light Chain, Dimer, Recombinant Humanized Anti-VEGF Monoclonal Antibody, rhuMab-VEGFCohort III (atezolizumab, bevacizumab)
CobimetinibCotellic, GDC-0973, MEK Inhibitor GDC-0973, XL518Cohort I (vemurafenib, cobimetinib, atezolizumab)
Nab-paclitaxelABI 007, ABI-007, Abraxane, Albumin-bound Paclitaxel, Albumin-Stabilized Nanoparticle Paclitaxel, Nanoparticle Albumin-bound Paclitaxel, Nanoparticle Paclitaxel, paclitaxel albumin-stabilized nanoparticle formulation, Protein-bound PaclitaxelCohort IV (nab-paclitaxel, atezolizumab, paclitaxel,)
PaclitaxelAnzatax, Asotax, Bristaxol, Praxel, Taxol, Taxol KonzentratCohort IV (nab-paclitaxel, atezolizumab, paclitaxel,)
VemurafenibBRAF (V600E) kinase inhibitor RO5185426, BRAF(V600E) Kinase Inhibitor RO5185426, PLX-4032, PLX4032, RG 7204, RG7204, RO 5185426, ZelborafCohort I (vemurafenib, cobimetinib, atezolizumab)

Purpose

This phase II trial studies how well atezolizumab in combination with chemotherapy works in treating patients with anaplastic or poorly differentiated thyroid cancer. Immunotherapy with monoclonal antibodies, such as atezolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Vemurafenib and cobimetinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Monoclonal antibodies, such as bevacizumab, may interfere with the ability of cancer cells to grow and spread. Drugs such as nab-paclitaxel and paclitaxel work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. This trial is being done to see if atezolizumab in combination with chemotherapy works better in treating patients with anaplastic or poorly differentiated thyroid cancer compared to standard treatments.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To determine if targeted therapy + atezolizumab (cohorts 1-3) will lead to improved
      overall survival (OS) in patients with anaplastic thyroid carcinoma (ATC).

      SECONDARY OBJECTIVES:

      I. To evaluate the safety and efficacy (Response Evaluation Criteria in Solid Tumors [RECIST]
      response rate, progression-free survival [PFS]) of targeted therapy + atezolizumab (cohorts
      1-3) in ATC and poorly differentiated thyroid cancer (PDTC).

      II. To determine the OS in patients with PDTC treated with targeted therapy + atezolizumab
      (cohorts 1-3).

      III. To determine the efficacy (RECIST response rate, progression-free survival [PFS]) and OS
      of ATC and PDTC patients treated with taxanes + atezolizumab (cohort 4).

      EXPLORATORY OBJECTIVES:

      I. To evaluate changes in the tumor-associated and systemic immune system biomarkers in ATC
      and PDTC patients treated with immunotherapy.

      OUTLINE: Patients are assigned to 1 of 4 cohorts.

      COHORT I (BRAF MUTATION): Patients receive vemurafenib orally (PO) twice daily (BID) on days
      1-21, cobimetinib PO once daily (QD) on days 1-21, and atezolizumab intravenously (IV) over
      30-60 minutes on days 1 and 15. Cycles repeat every 28 days in the absence of disease
      progression and unacceptable toxicity.

      COHORT II (RAS, NF1, OR NF2 MUTATION including patients with MAPK activating mutations at or
      above MEK): Patients receive cobimetinib PO QD on days 1-21 and atezolizumab IV over 30-60
      minutes on days 1 and 15. Cycles repeat every 28 days in the absence of disease progression
      and unacceptable toxicity.

      COHORT III (NON-BRAF/NON-RAS MUTATION): Patients receive atezolizumab IV over 30-60 minutes
      and bevacizumab IV over 60-90 minutes on day 1. Cycles repeat every 21 days in the absence of
      disease progression and unacceptable toxicity.

      COHORT IV: Patients receive nab-paclitaxel IV over 30 minutes on days 1, 8, and 15 and
      atezolizumab IV over 30-60 minutes on day 1. Patients may receive paclitaxel IV over 30
      minutes on day 1 as a substitute for nab-paclitaxel. Cycles repeat every 21 days in the
      absence of disease progression and unacceptable toxicity.

      After completion of study treatment, patients are followed up every 3 months for years 1-2,
      every 6 months for years 3-4, then yearly thereafter.
    

Trial Arms

NameTypeDescriptionInterventions
Cohort I (vemurafenib, cobimetinib, atezolizumab)ExperimentalPatients receive vemurafenib PO BID on days 1-21, cobimetinib PO QD on days 1-21, and atezolizumab IV over 30-60 minutes on days 1 and 15. Cycles repeat every 28 days in the absence of disease progression and unacceptable toxicity.
  • Atezolizumab
  • Cobimetinib
  • Vemurafenib
Cohort II (atezolizumab, cobimetinib)ExperimentalPatients receive cobimetinib PO QD on days 1-21 and atezolizumab IV over 30-60 minutes on days 1 and 15. Cycles repeat every 28 days in the absence of disease progression and unacceptable toxicity.
  • Atezolizumab
  • Cobimetinib
Cohort III (atezolizumab, bevacizumab)ExperimentalPatients receive atezolizumab IV over 30-60 minutes and bevacizumab IV over 60-90 minutes on day 1. Cycles repeat every 21 days in the absence of disease progression and unacceptable toxicity.
  • Atezolizumab
  • Bevacizumab
Cohort IV (nab-paclitaxel, atezolizumab, paclitaxel,)ExperimentalPatients receive nab-paclitaxel IV over 30 minutes on days 1, 8, and 15 and atezolizumab IV on day 1 over 30-60 minutes. Patients may receive paclitaxel IV over 30 minutes on day 1 as a substitute for nab-paclitaxel. Cycles repeat every 21 days in the absence of disease progression and unacceptable toxicity.
  • Atezolizumab
  • Nab-paclitaxel
  • Paclitaxel

Eligibility Criteria

        Inclusion Criteria:

          -  Histologically confirmed anaplastic thyroid or poorly differentiated thyroid
             carcinomas.

          -  Patients deemed to have unresectable locoregional disease or metastatic disease.
             Patients who are unwilling to undergo surgery or external beam radiation are also
             eligible.

          -  Patients with poorly differentiated thyroid cancer must have at least one target
             lesion by RECIST version 1.1. This is not a requirement for ATC patients.

          -  Total bilirubin =<1.5 x upper limit of normal (ULN). Total bilirubin: 3 x ULN for
             patients with Gilbert's syndrome.

          -  Aspartate aminotransferase (AST) serum glutamic-oxaloacetic transaminase (SGOT) /
             alanine aminotransferase (ALT) serum glutamate pyruvate transaminase (SGPT) =< 2.5 x
             ULN, (5 x ULN for patients with concurrent liver metastases).

          -  Serum creatinine =< within 1.5 x ULN.

          -  Absolute neutrophil count (ANC) >= 1.0 x 10^9 /L.

          -  Platelets (PLT) >= 100 x 10^9 /L.

          -  For patients receiving therapeutic anticoagulation: stable anticoagulant regimen and
             stable international normalized ratio (INR) during the 28 days immediately preceding
             initiation of study treatment.

          -  Subjects must be willing to undergo tumor biopsy prior to and after treatment with
             atezolizumab, unless in the opinion of the treating physician, a biopsy is not
             feasible or safe.

          -  Eastern Cooperative Oncology Group (ECOG) performance score (PS) =< 2.

          -  Age and reproductive status:

               -  Males and females, >=18 years. Women of childbearing potential (WOCBP) must have
                  a negative serum or urine pregnancy test within 14 days prior to the start of
                  study drug and must use effective contraceptives throughout the duration of the
                  study. Males who are sexually active with WOCBP must agree to use effective
                  contraception throughout the duration of the study. Azoospermic males and WOCBP
                  who are continuously not heterosexually active are exempt from contraceptive
                  requirements.

                    -  A Women of childbearing potential (WOCBP) is defined as any female who has
                       experienced menarche and who has not undergone surgical sterilization
                       (hysterectomy or bilateral oophorectomy) and is not postmenopausal.
                       Menopause is defined as 12 months of amenorrhea in a woman over age 45 years
                       in the absence of other biological or physiological causes.

          -  Ability to provide informed consent.

          -  ADDITIONAL INCLUSION CRITERIA FOR BRAF MUTATION (COHORT 1): Patients with a BRAFV600E
             mutation being considered for the triplet combination (vemurafenib + cobimetinib +
             atezolizumab) must meet the following end organ function criteria:

          -  COHORT 1: ANC >= 1.5 × 10^9 /L without granulocyte colony-stimulating factor support.

          -  COHORT 1: WBC count >= 2.5 x 10^9 /L.

          -  COHORT 1: Lymphocyte count >= 0.5 x 10^9/L.

          -  COHORT 1: Platelet count >= 100 × 10^9 /L without transfusion.

          -  COHORT 1: Hemoglobin >= 9.0 g/L without transfusion.

          -  COHORT 1: Serum albumin > =2.5 g/L

          -  COHORT 1: Total bilirubin =< 1.5 x ULN

          -  COHORT 1: AST and ALT =< 2.0 x ULN

          -  COHORT 1: Alkaline phosphatase (ALP) =< 2.5 x ULN or, for patients with documented
             liver or bone metastases, ALP =< 5 x ULN

          -  COHORT 1: Serum creatinine =< 1.5 x ULN or creatinine clearance (CrCl) >= 40 mL/min on
             the basis of measured CrCl from a 24-hour urine collection or Cockcroft-Gault
             glomerular filtration rate estimation. Patients with BRAF mutation may be screened for
             eligibility in cohorts 2, 3, or 4 (in this order of preference) if they do not meet
             the entry criteria for cohort 1.

        Exclusion Criteria:

          -  Subjects with an active, known or suspected autoimmune disease. Subjects with type I
             diabetes mellitus on stable insulin regimen, hypothyroidism only requiring hormone
             replacement, skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring
             systemic treatment, or conditions not expected to recur in the absence of an external
             trigger are permitted to enroll.

          -  For patients not receiving therapeutic anticoagulation: INR or partial thromboplastin
             time (aPTT) > 1.5 x ULN within 28 days prior to initiation of study treatment.

          -  Prior treatment with anti-PD-1, or anti-PD-L1 therapeutic antibody or pathway
             targeting agents. Patients who have received prior treatment with anti-CTLA-4 may be
             enrolled, provided the following requirements are met: Minimum of 12 weeks from the
             first dose of anti-CTLA-4 and > 6 weeks from the last dose, and no history of severe
             immune-related adverse effects from anti-CTLA 4 (National Cancer Institute [NCI]
             Common Terminology Criteria for Adverse Events [CTCAE] grade 3 and 4).

          -  Known clinically significant liver disease, including active viral, alcoholic, or
             other hepatitis; cirrhosis; fatty liver; and inherited liver disease.

          -  History of human immunodeficiency virus (HIV) infection or active hepatitis B (chronic
             or acute) or hepatitis C infection Patients with past or resolved hepatitis B
             infection (defined as having a negative hepatitis B surface antigen [HBsAg] test and a
             positive anti-HBc [antibody to hepatitis B core antigen] antibody test) are eligible.
             However, patients with past or resolved hepatitis B virus (HBV) should be monitored
             for reactivation by a specialist. Patients positive for hepatitis C virus (HCV)
             antibody are eligible only if polymerase chain reaction (PCR) is negative for HCV
             ribonucleic acid (RNA).

          -  Pregnant or lactating women. All pre-menopausal women being screened must have a
             negative serum pregnancy test within 14 days prior to commencement of dosing. Women of
             non-childbearing potential may be included if they are either surgically sterile or
             have been postmenopausal for >= 1 year. Fertile men and women must use an effective
             method of contraception during treatment and for at least 6 months after completion of
             treatment as directed by their physician.

          -  Untreated brain metastases.

          -  Chemotherapy within 21 days of enrollment with the exception of paclitaxel or
             nab-paclitaxel (Abraxane). Patients who have received one course of these agents prior
             to study entry are eligible. (One course of weekly paclitaxel or nab-paclitaxel is 3
             doses. One course of every 3 week dosing of paclitaxel or nab-paclitaxel is 1 dose).
             Patients who have received prior radiosensitizing chemotherapy are eligible.

          -  The use of corticosteroids is not allowed for 10 days prior to initiation of
             atezolizumab except patients who are taking steroids for physiological replacement.
             Inhaled or topical steroids, and adrenal replacement steroid doses are permitted in
             the absence of active autoimmune disease. This does not apply to patients receiving
             steroids as pre-medications for paclitaxel administration.

          -  Grade >= 2 uncontrolled hypertension (patients with a history of hypertension
             controlled with anti-hypertensive medication to Grade =< 1 are eligible).

          -  ADDITIONAL EXCLUSION CRITERIA FOR non-BRAF/non-RAS MUTATION (COHORT 3):

               -  Patients with clinically significant hemoptysis or tumor bleeding within two
                  weeks prior to first dose of targeted therapy.

               -  Patients with suspected tracheal or esophageal invasion are excluded from cohort
                  3 due to the high risk of trachealesophageal fistula. Patients excluded from
                  cohort 3 may be enrolled on taxane + atezolizumab cohort (cohort 4).

          -  ADDITIONAL EXCLUSION CRITERIA FOR COHORTS 1 and 2: Ocular Exclusion Criteria for
             vemurafenib and cobimetinib containing cohorts—cohorts 1 and 2. (However, these
             patients may be assigned other cohorts if they do not meet the ocular exclusion
             criteria): History of or evidence of retinal pathology on ophthalmologic examination
             that is considered a risk factor for neurosensory retinal detachment, central serous
             chorioretinopathy, retinal vein occlusion (RVO), or neovascular macular degeneration
             Patients will be excluded from participation in cohorts 1 and 2 if they currently are
             known to have any of the following risk factors for RVO:

               -  History of serous retinopathy.

               -  History of retinal vein occlusion.

               -  History of ongoing serous retinopathy or RVO.

          -  ADDITIONAL EXCLUSION CRITERIA FOR PATIENTS IN COHORT 1
             (vemurafenib+cobimetinib+atezolizumab): History of clinically significant cardiac
             dysfunction, including the following:

               -  Mean (average of triplicate measurements) QTc interval corrected using
                  Fridericia's method >= 480 ms at screening, or uncorrectable abnormalities in
                  serum electrolytes (sodium, potassium, calcium, magnesium, and phosphorus).

          -  ADDITIONAL EXCLUSION CRITERIA FOR PATIENTS IN COHORTS 1 and 2 (cobimetinib-containing
             cohorts):

               -  Unstable angina, or new-onset angina within 3 months prior to initiation of study
                  treatment.

               -  Symptomatic congestive heart failure, defined as New York Heart Association Class
                  II or higher.

               -  Myocardial infarction within 3 months prior to initiation of study treatment.

               -  Left ventricular ejection fraction below the institutional lower limit of normal
                  or below 50%, whichever is lower.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Overall survival (OS) with targeted therapy + atezolizumab in cohorts 1 and 3 with anaplastic thyroid carcinoma (ATC)
Time Frame:5 years
Safety Issue:
Description:Overall survival is defined as the time from start date of cohort specific treatment to death from any cause will be estimated using the Kaplan-Meier method.

Secondary Outcome Measures

Measure:Efficacy determined per Response Evaluation Criteria for Solid Tumors (RECIST) of targeted therapy + atezolizumab in Cohorts 1-3 with anaplastic thyroid carcinoma (ATC) and poorly differentiated thyroid cancer (PDTC)
Time Frame:5 years
Safety Issue:
Description:
Measure:Efficacy determined per immune related (ir)RECIST of targeted therapy + atezolizumab in Cohorts 1-3 with anaplastic thyroid carcinoma (ATC) and poorly differentiated thyroid cancer (PDTC)
Time Frame:5 years
Safety Issue:
Description:
Measure:Efficacy determined per RECIST of taxanes + atezolizumab in cohort 4 with poorly differentiated thyroid cancer (PDTC)
Time Frame:5 years
Safety Issue:
Description:
Measure:Progression-free survival anaplastic thyroid carcinoma (ATC) and poorly differentiated thyroid cancer (PDTC)
Time Frame:5 years
Safety Issue:
Description:Progression-free survival defined as the time from start date of cohort specific treatment to progression or death (whichever occurs first) will be estimated using the Kaplan-Meier method.
Measure:Adverse events of targeted therapy + atezolizumab in cohorts 1-3 with anaplastic thyroid carcinoma (ATC) and poorly differentiated thyroid cancer (PDTC)
Time Frame:90 days after study drugs stopped
Safety Issue:
Description:Adverse events recorded per The Common Terminology Criteria for Adverse Events (CTCAE).
Measure:Adverse events of taxanes + atezolizumab in cohort 4 with poorly differentiated thyroid cancer (PDTC)
Time Frame:90 days after study drugs stopped
Safety Issue:
Description:Adverse events recorded per CTCAE.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:M.D. Anderson Cancer Center

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