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Atezolizumab Combinations With Chemotherapy for Anaplastic and Poorly Differentiated Thyroid Carcinomas

This study is currently recruiting participants.
Verified October 2017 by M.D. Anderson Cancer Center
Sponsor:
ClinicalTrials.gov Identifier:
NCT03181100
First Posted: June 8, 2017
Last Update Posted: October 6, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
Collaborator:
Genentech, Inc.
Information provided by (Responsible Party):
M.D. Anderson Cancer Center
  Purpose

Objectives:

Primary:

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

Secondary:

  1. To evaluate the safety and efficacy (RECIST response rate, progression-free survival [PFS]) of targeted therapy + atezolizumab (cohorts 1-3) in ATC and poorly differentiated thyroid cancer (PDTC).
  2. To determine the OS in patients with PDTC treated with targeted therapy + atezolizumab (cohorts 1-3).
  3. To determine the efficacy (RECIST response rate, progression-free survival [PFS]) and OS of ATC and PDTC patients treated with taxanes + atezolizumab (cohort 4)

Condition Intervention Phase
Malignant Neoplasms of Thyroid and Other Endocrine Glands Anaplastic Thyroid Carcinoma Poorly Differentiated Thyroid Cancer Drug: Nab-paclitaxel - INDUCTION COHORT Drug: Paclitaxel - INDUCTION COHORT Drug: Vemurafenib - COHORT 1 Drug: Cobimetinib - COHORT 1 Drug: Atezolizumab - COHORT 1 Drug: Bevacizumab - COHORT 3 Drug: Nab-paclitaxel - COHORT 4 Drug: Paclitaxel - COHORT 4 Drug: Cobimetinib - COHORT 2 Drug: Atezolizumab - COHORT 2 Drug: Atezolizumab - COHORT 3 Drug: Atezolizumab - COHORT 4 Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Atezolizumab Combinations With Chemotherapy for Anaplastic and Poorly Differentiated Thyroid Carcinomas

Resource links provided by NLM:


Further study details as provided by M.D. Anderson Cancer Center:

Primary Outcome Measures:
  • Overall Survival (OS) with Targeted Therapy + Atezolizumab in Cohorts 1 and 3 with Anaplastic Thyroid Carcinoma (ATC) [ Time Frame: 5 years ]
    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:
  • Efficacy Determined per RECIST of Targeted Therapy + Atezolizumab in Cohorts 1-3) with Anaplastic Thyroid Carcinoma (ATC) and Poorly Differentiated Thyroid Cancer (PDTC) [ Time Frame: 5 years ]
  • Efficacy Determined per irRECIST of Targeted Therapy + Atezolizumab in Cohorts 1-3 with Anaplastic Thyroid Carcinoma (ATC) and Poorly Differentiated Thyroid Cancer (PDTC) [ Time Frame: 5 years ]
  • Efficacy Determined per RECIST of Taxanes + Atezolizumab in Cohort 4 with Poorly Differentiated Thyroid Cancer (PDTC) [ Time Frame: 5 years ]
  • Progression-Free Survival Anaplastic Thyroid Carcinoma (ATC) and Poorly Differentiated Thyroid Cancer (PDTC) [ Time Frame: 5 years ]
    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.

  • 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 ]
    Adverse events recorded per The Common Terminology Criteria for Adverse Events (CTCAE).

  • Adverse Events of Taxanes + Atezolizumab in Cohort 4 with Poorly Differentiated Thyroid Cancer (PDTC) [ Time Frame: 90 days after study drugs stopped ]
    Adverse events recorded per The Common Terminology Criteria for Adverse Events (CTCAE).


Estimated Enrollment: 50
Actual Study Start Date: July 27, 2017
Estimated Study Completion Date: July 2023
Estimated Primary Completion Date: July 2023 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Induction Cohort

Induction phase with single agent taxanes: This phase is optional and serves only as a bridge to mutation-driven treatment assignment. For example, if molecular testing is readily available, patients may be assigned to the mutation-driven cohorts and do not require induction phase.

- Nab-paclitaxel 100 mg/m2 by vein weekly for up to 3 doses (preferred)

OR

- Paclitaxel 80 mg/m2 by vein weekly for up to 3 doses

Drug: Nab-paclitaxel - INDUCTION COHORT
INDUCTION COHORT: Nab-paclitaxel 100 mg/m2 by vein weekly for up to 3 doses.
Other Names:
  • Paclitaxel (protein bound)
  • Abraxane
  • ABI-007
Drug: Paclitaxel - INDUCTION COHORT
INDUCTION COHORT: Paclitaxel 80 mg/m2 by vein weekly for up to 3 doses.
Other Name: Taxol
Experimental: Cohort 1
Cohort 1BRAF mutant: Vemurafenib 960 mg by mouth twice a day (day 1-21) + Cobimetinib 60 mg by mouth every day (day 1-21) run-in before starting Atezolizumab. Vemurafenib dose reduced to 720 mg twice a day (at cycle 1 day 21) and Cobimetinib 60 mg taken on days 1-21. Atezolizumab 840 mg by vein on Day 1 and Day 15 in a 28-day cycle, started on Cycle 1, Day 1. Patients who have > grade 3 LFTs (AST, ALT or total bilirubin) will not receive Atezolizumab but may continue on Vemurafenib + Cobimetinib with dose reduction. If after dose reductions, the LFTs are below grade 3, patient may start Atezolizumab.
Drug: Vemurafenib - COHORT 1
COHORT 1: Vemurafenib 960 mg by mouth twice a day (Day 1-21). Vemurafenib dose reduced to 720 mg twice a day (at cycle 1 day 21).
Other Names:
  • PLX4032
  • RO5185426
Drug: Cobimetinib - COHORT 1
COHORT 1: Cobimetinib 60 mg by mouth every day (Day 1-21) run-in before starting Atezolizumab.
Drug: Atezolizumab - COHORT 1
COHORT 1: Atezolizumab 840 mg by vein on Day 1 and Day 15 in a 28 day cycle, started on Cycle 1, Day 1. Patients who have > grade 3 LFTs (AST, ALT or total bilirubin) will not receive Atezolizumab but may continue on Vemurafenib + Cobimetinib with dose reduction. If after dose reductions, the LFTs are below grade 3, patient may start Atezolizumab.
Other Name: MPDL3280A
Experimental: Cohort 2
Cohort 2 RAS mutant: Atezolizumab 840 mg by vein on Day 1 and Day 15 in a 28-day cycle. Cobimetinib 60 mg by mouth on Days 1-21.
Drug: Cobimetinib - COHORT 2
COHORT 2: Cobimetinib 60 mg by mouth on Days 1−21.
Drug: Atezolizumab - COHORT 2
COHORT 2: Atezolizumab 840 mg by vein on Day 1 and Day 15 in a 28 day cycle.
Other Name: MPDL3280A
Experimental: Cohort 3
Cohort 3 Non-BRAF/non-RAS mutant: Atezolizumab 1200 mg by vein every 21 days plus Bevacizumab 15 mg/kg by vein every 21 days in a 21-day cycle.
Drug: Bevacizumab - COHORT 3
COHORT 3: Bevacizumab 15 mg/kg by vein every 21 days in a 21-day cycle.
Other Names:
  • Avastin
  • Anti-VEGF monoclonal antibody
  • rhuMAb-VEGF
Drug: Atezolizumab - COHORT 3
COHORT 3: Atezolizumab 1200 mg by vein every 21 days.
Other Name: MPDL3280A
Experimental: Cohort 4

Cohort 4: Atezolizumab 1200 mg by vein every 21 days.

If participant receives Nab-paclitaxel it will be given at 100 mg/m2 by vein on days 1, 8, and 15.

If participant receives Paclitaxel, it will be given at 175 mg/m2 it by vein every 21 days.

Drug: Nab-paclitaxel - COHORT 4
COHORT 4: Nab-paclitaxel 100 mg/m2 by vein on Days 1, 8, and 15.
Other Names:
  • Paclitaxel (protein bound)
  • Abraxane
  • ABI-007
Drug: Paclitaxel - COHORT 4
COHORT 4: Paclitaxel may be substituted for nab-paclitaxel but nab-paclitaxel is preferred. Dose of Paclitaxel is 175 mg/m2 by vein every 21 days.
Other Name: Taxol
Drug: Atezolizumab - COHORT 4
COHORT 4: Atezolizumab 1200 mg by vein every 21 days.
Other Name: MPDL3280A

  Show Detailed Description

  Eligibility

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Histologically confirmed anaplastic thyroid or poorly differentiated thyroid carcinomas.
  2. Patients deemed to have unresectable locoregional disease or metastatic disease. Patients who are unwilling to undergo surgery or external beam radiation are also eligible.
  3. Patients with poorly differentiated thyroid cancer must have at least one target lesion by RECIST v1.1. This is not a requirement for ATC patients.
  4. Total bilirubin </=1.5 x upper limit of normal (ULN). Patients with Gilbert's syndrome are excluded from this requirement. AST (SGOT)/ALT (SGPT) </=2.5 x ULN, (5 x ULN for patients with concurrent liver metastases). Serum creatinine </= within 1.5 x ULN. ANC >/= 1.0 x 10^9/L; PLT >/= 100 x 10^9/L.
  5. For patients receiving therapeutic anticoagulation: stable anticoagulant regimen and stable INR during the 28 days immediately preceding initiation of study treatment
  6. 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.
  7. ECOG PS</=2
  8. Age >/= 18 years.
  9. Age and Reproductive Status a) 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.
  10. Ability to provide informed consent.
  11. 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: ANC >/= 1.5 × 10^9/L without granulocyte colony-stimulating factor support, WBC count >/= 2.5 × 10^9/L, Lymphocyte count >/= 0.5 × 10^9/L, Platelet count >/= 100 × 10^9/L without transfusion, Hemoglobin >/= 9.0 g/L without transfusion.
  12. ADDITIONAL INCLUSION CRITERIA FOR BRAF MUTATION (COHORT 1): Serum albumin >/=2.5 g/L, Total bilirubin </= 1.5 × ULN, AST and ALT </= 2.0 × ULN, Alkaline phosphatase (ALP) </= 2.5 × ULN or, for patients with documented liver or bone metastases, ALP </= 5 × ULN, Serum creatinine </= 1.5 × 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: CrCl = ((140 - age) / (serum creatinine in mg/dL)) × (weight in kg) (× 0.85 if female)/ 72). 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.
  13. ADDITIONAL INCLUSION CRITERIA FOR BRAF and RAS MUTATION (COHORTS 1 and 2): Ability to swallow pills. Patients may be assigned to bevacizumab + atezolizumab cohort 3 or taxane + atezolizumab cohort 4 (in this order of preference) if they are unable to swallow pills

Exclusion Criteria:

  1. 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.
  2. For patients not receiving therapeutic anticoagulation: INR or aPTT >1.5 x ULN within 28 days prior to initiation of study treatment
  3. 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 (NCI CTCAE Grade 3 and 4)
  4. Known clinically significant liver disease, including active viral, alcoholic, or other hepatitis; cirrhosis; fatty liver; and inherited liver disease.
  5. History of 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 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 RNA.
  6. 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.
  7. Untreated brain metastases.
  8. 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.
  9. 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.
  10. Grade >/= 2 uncontrolled hypertension (patients with a history of hypertension controlled with anti-hypertensive medication to Grade </= 1 are eligible)
  11. ADDITIONAL EXCLUSION CRITERIA FOR non-BRAF/non-RAS MUTATION (COHORT 3): a. Patients with clinically significant hemoptysis or tumor bleeding within two weeks prior to first dose of targeted therapy. b. Patients with suspected tracheal or esophageal invasion are excluded from cohort 3 due to the high risk of tracheooesophageal fistula. Patients excluded from cohort 3 may be enrolled on taxane + atezolizumab cohort (cohort 4).
  12. 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: a. Glaucoma with intraocular pressure >/= 21 mmHg b. Grade >/= 2 serum cholesterol c. Grade >/= 2 hypertriglyceridemia d. Grade >/=2 or symptomatic hyperglycemia (fasting)
  13. ADDITIONAL EXCLUSION CRITERIA FOR PATIENTS IN COHORT 1 (vemurafenib+cobimetinib+atezolizumab): Cardiac Exclusion Criteria: History of clinically significant cardiac dysfunction, including the following: a. Unstable arrhythmia b.History of congenital long QT syndrome c.Mean (average of triplicate measurements) QTc interval corrected using Fridericia's method >/= 450 ms at screening, or uncorrectable abnormalities in serum electrolytes (sodium, potassium, calcium, magnesium, and phosphorus)
  14. ADDITIONAL EXCLUSION CRITERIA FOR PATIENTS IN COHORTS 1 and 2 (cobimetinib-containing cohorts): Cardiac Exclusion Criteria: a. Unstable angina, or new-onset angina within 3 months prior to initiation of study treatment b. Symptomatic congestive heart failure, defined as New York Heart Association Class II or higher c. Myocardial infarction within 3 months prior to initiation of study treatment d. Left ventricular ejection fraction below the institutional lower limit of normal or below 50%, whichever is lower
  Contacts and Locations
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03181100


Contacts
Contact: Maria E. Cabanillas, MD 713-792-2841 CR_Study_Registration@mdanderson.org
Contact: Debra Nichols, CCRP, RN 713-792-0839

Locations
United States, Texas
University of Texas MD Anderson Cancer Center Recruiting
Houston, Texas, United States, 77030
Contact: Clinical Research Operations       CR_Study_Registration@mdanderson.org   
Contact       mcabani@mdanderson.org   
Sponsors and Collaborators
M.D. Anderson Cancer Center
Genentech, Inc.
Investigators
Principal Investigator: Maria E. Cabanillas, MD M.D. Anderson Cancer Center
  More Information

Additional Information:
Responsible Party: M.D. Anderson Cancer Center
ClinicalTrials.gov Identifier: NCT03181100     History of Changes
Other Study ID Numbers: 2016-0916
NCI-2017-01519 ( Registry Identifier: NCI CTRP )
First Submitted: June 6, 2017
First Posted: June 8, 2017
Last Update Posted: October 6, 2017
Last Verified: October 2017

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by M.D. Anderson Cancer Center:
Vemurafenib
PLX4032
Malignant neoplasms of thyroid and other endocrine glands
Anaplastic thyroid carcinoma
ATC
Poorly differentiated thyroid cancer
PDTC
Nab-paclitaxel
Paclitaxel (protein bound)
Abraxane
ABI-007
Paclitaxel
Taxol
R05185426
Cobimetinib
Atezolizumab
MPDL3280A
Bevacizumab
Avastin
Anti-VEGF monoclonal antibody
rhuMAb-VEGF
BRAF
BRAF inhibitor
MEK
MEK inhibitor
Immunotherapy
Targeted therapy

Additional relevant MeSH terms:
Vemurafenib
Carcinoma
Thyroid Diseases
Thyroid Neoplasms
Neoplasms
Thyroid Carcinoma, Anaplastic
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Endocrine System Diseases
Endocrine Gland Neoplasms
Neoplasms by Site
Head and Neck Neoplasms
Paclitaxel
Atezolizumab
Albumin-Bound Paclitaxel
Bevacizumab
Antibodies
Antibodies, Monoclonal
Antineoplastic Agents, Phytogenic
Antineoplastic Agents
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Growth Substances
Physiological Effects of Drugs
Growth Inhibitors
Immunologic Factors