Thyroid Cancer
Conditions
Keywords
Thyroid Cancer
Brief summary
This research study is studying nivolumab, an investigational drug, in combination with ipilimumab, also an investigational drug, as a possible treatment for thyroid cancer. The drugs involved in this study are: * Nivolumab (Opdivo™) * Ipilimumab (Yervoy™)
Detailed description
This research study is a Phase 2 clinical trial. Phase 2 clinical trials test the safety and effectiveness of an investigational intervention to learn whether the intervention works in treating a specific disease. Investigational means that the intervention is being studied. The purpose of this study is to evaluate effectiveness (how well the drug/s work) of nivolumab combined with ipilimumab. Nivolumab and ipilimumab are types of immunotherapy. Immunotherapy works by encouraging the body's own immune system to attack cancer cells. Nivolumab has been approved by the US Food and Drug Administration (FDA) for the treatment of metastatic melanoma (a type of skin cancer), and specific types of previously treated advanced lung and kidney cancers. Ipilimumab is approved by the FDA for the treatment of metastatic melanoma. The combination of nivolumab and ipilimumab is now FDA approved as treatment for patients with metastatic melanoma. However, the use of nivolumab as well as ipilimumab alone or in combination for the treatment of patients with thyroid cancer is not approved
Interventions
DRUGNivolumab
Ipilimumab are types of immunotherapy Immunotherapy works by encouraging the body's own immune system to attack cancer cells.
DRUGIpilimumab
Nivolumab are types of immunotherapy. Immunotherapy works by encouraging the body's own immune system to attack cancer cells.
Sponsors
Bristol-Myers Squibb
Dana-Farber Cancer Institute
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Inclusion * Metastatic, RAI refractory, differentiated thyroid cancer (including papillary and follicular thyroid cancer and their sub-types such as Hurthle cell thyroid cancer as well as poorly differentiated thyroid cancer), with progression within 13 months prior to study registration. RAI refractoriness is defined as absence of uptake of RAI on either a low-dose diagnostic test or a post-treatment RAI scan in measurable lesions or radiographic progression of disease within 12 months of the last course of RAI treatment despite the recorded uptake of RAI with that previous therapy or having a cumulative lifetime administered dose of greater than 600mCi. * Exploratory cohort: incurable medullary thyroid cancer with prior tyrosine kinase inhibitor (TKI) failure and progression within 13 months prior to enrollment (10 patients) and anaplastic thyroid cancer (7 patients) * Any number of lines of prior treatment are allowed * Any line of prior treatment for patients under 65y, over 65y must have at least one prior line of TKI treatment * Age 18 years or older * ECOG performance status ≤2 (Karnofsky ≥60%, see Appendix A) * Participants must have normal organ and marrow function as defined below: * Screening laboratory values must meet the following criteria and should be obtained within 21 days prior to randomization/registration * WBC ≥ 2000/μL * Neutrophils ≥ 1500/μL * Platelets ≥ 100 x103/μL * Hemoglobin \> 9.0 g/dL * Serum creatinine ≤ 1.5 x ULN or creatinine clearance (CrCl) ≥ 40 mL/min (if using the Cockcroft-Gault formula below): * Female CrCl = (140 - age in years) x weight in kg x 0.85 72 x serum creatinine in mg/dL * Male CrCl = (140 - age in years) x weight in kg x 1.00 72 x serum creatinine in mg/dL * AST/ALT ≤ 3 x ULN * Total Bilirubin ≤ 1.5 x ULN (except subjects with Gilbert Syndrome, who can have total bilirubin \< 3.0 mg/dL) * Ability to understand and the willingness to sign a written informed consent document. * Women of childbearing potential (WOCBP) must use appropriate method(s) of contraception. WOCBP should use an adequate method to avoid pregnancy for 23 weeks (30 days plus the time required for nivolumab to undergo five half-lives) after the last dose of investigational drug * Women of childbearing potential must have a negative serum or urine pregnancy test (minimum sensitivity 25 iu/l or equivalent units of hcg) within 24 hours of the first dose of the study drug * Women of childbearing potential is defined as any female who has experienced menarche and who has not undergone surgical sterilization (hysterectomy or bilateral oophorectomy) or who is not postmenopausal. Menopause is defined clinically as 12 months of amenorrhea in a woman over 45 in the absence of other biological or physiological causes. In addition, women under the age of 55 must have a documented serum follicle stimulating hormone (FSH) level less than 40 mIU/mL. * Men who are sexually active with WOCBP must use any contraceptive method with a failure rate of less than 1% per year Men receiving nivolumab and who are sexually active with WOCBP will be instructed to adhere to contraception for a period of 31 weeks after the last dose of investigational product Women who are not of childbearing potential (ie, who are postmenopausal or surgically sterile as well as azoospermic men do not require contraception Exclusion * Patients should be excluded if they have an active, known or suspected autoimmune disease. Subjects are permitted to enroll if they have vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger * Patients should be excluded if they have a condition requiring systemic treatment with either corticosteroids (\> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration. Inhaled or topical steroids and adrenal replacement doses \> 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease. * As there is potential for hepatic toxicity with nivolumab or nivolumab/ipilimumab combinations, drugs with a predisposition to hepatoxicity should be used with caution in patients treated with nivolumab-containing regimen. * Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier. * Patients who are receiving any other investigational agents. * Patients with activebrain metastases should be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events. * Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Best Overall Response Rate | Median (range) treatment duration (days) of 163.0 (21.0-734.0) for DTC cohort, for MTC cohort was 58.0 (30.0-252.0), and for ATC cohort 135.5 (10.0-735.0). | Best overall response rate is defined as the percentage of participants who achieved Complete response (CR) or partial response (PR) on treatment based on RECIST 1.1 criteria. Per RECIST 1.1 for target lesions: CR is complete disappearance of all target lesions and PR is at least a 30% decrease in the sum of longest diameter (LD) of target lesions, taking as reference baseline sum LD. PR or better overall response assumes at a minimum incomplete response/stable disease (SD) for the evaluation of non-target lesions and absence of new lesions. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Median Progression Free Survival | Median (range) follow-up (months) for DTC cohort was 24.0 (1.84 - 24.7), for MTC cohort was 24.0 (23.0-24.2), and for ATC cohort was 22.2 (0.46 - 26.1). | Progression-Free Survival (PFS) based on Kaplan-Meier methodology is defined as the time from randomization (or registration) to the earlier of progression or death due to any cause. Participants alive without disease progression are censored at date of last disease evaluation. Participants alive without PD were censored at the earliest of the date of the last disease evaluation or start of new anticancer therapy. Per RECIST 1.1 for target lesions: PD is at least a 20% increase in sum LD, taking as reference the smallest sum on study with at least 5 mm absolute increase. For non-target lesions, progression-free means no new lesions or unequivocal progression on existing non-target lesions or not evaluated. |
| Overall Survival at 2 Years (OS2) | Median (range) follow-up (months) for DTC cohort was 24.0 (1.84 - 24.7), for MTC cohort was 24.0 (23.0-24.2), and for ATC cohort was 22.2 (0.46 - 26.1). | Overall Survival is the percent probability estimate at 2 years based on Kaplan-Meier methodology. OS is defined as the time from randomization (or registration) to death due to any cause, or censored at date last known alive. |
| Treatment-Related Adverse Events Rate | AEs were assessed every two weeks on treatment and within 30 days after the last dose. Median (range) treatment duration (days) of 163.0 (21.0-734.0) for DTC cohort, for MTC cohort was 58.0 (30.0-252.0), and for ATC cohort 135.5 (10.0-735.0). | Treatment-related adverse events rate was defined as the proportion of participants who experienced an adverse event with treatment attribution of possible, probable or definite, including all grades based on the Common Toxicity Criteria for Adverse Events Version 4.0 (CTCAEv4) as reported on case report forms. |
Countries
United States
Participant flow
Recruitment details
Patients enrolled from October 2017 to July 2019.
Pre-assignment details
Per protocol order in sequential design was not expected to impact efficacy rather was for exploratory correlative analyses.
Participants by arm
| Arm | Count |
|---|---|
| DTC - Nivolumab Alone for Two Weeks Differentiated Thyroid Cancer (DTC) participants received Ipilimumab 1mg/kg q6 weeks via IV infusion, starting two weeks after Nivolumab 3mg/kg q6 weeks. | 16 |
| DTC - Ipilimumab Alone for Two Weeks Differentiated Thyroid Cancer (DTC) participants received Nivolumab 3mg/kg q6 weeks via IV infusion, starting two weeks after Ipilimumab 1mg/kg q6 weeks. | 16 |
| MTC - Nivolumab Alone for Two Week Medullary Thyroid Cancer (MTC)participants received Ipilimumab 1mg/kg q6 weeks via IV infusion, starting two weeks after Nivolumab 3mg/kg q6 weeks. | 3 |
| MTC - Ipilimumab Alone for Two Weeks Medullary Thyroid Cancer (MTC) participants received Nivolumab 3mg/kg q6 weeks via IV infusion, starting two weeks after Ipilimumab 1mg/kg q6 weeks. | 4 |
| ATC - Nivolumab Alone for Two Week Anaplastic Thyroid Cancer (ATC) received Ipilimumab 1mg/kg q6 weeks via IV infusion, starting two weeks after Nivolumab 3mg/kg q6 weeks. | 2 |
| ATC - Ipilimumab Alone for Two Week Anaplastic Thyroid Cancer (ATC) received Nivolumab 3mg/kg q6 weeks via IV infusion, starting two weeks after Ipilimumab 1mg/kg q6 weeks. | 4 |
| ATC - Ipilimumab + Nivolumab Anaplastic Thyroid Cancer (ATC) received Nivolumab 3mg/kg q6 weeks and Ipilimumab 1mg/kg q6 weeks via IV infusion. | 4 |
| Total | 49 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 |
|---|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 2 | 2 | 0 | 1 | 1 | 0 | 2 |
| Overall Study | Death | 0 | 1 | 0 | 0 | 0 | 0 | 0 |
| Overall Study | Never start treatment | 1 | 0 | 0 | 0 | 0 | 0 | 0 |
| Overall Study | Over enrollment | 0 | 2 | 0 | 0 | 0 | 0 | 0 |
| Overall Study | Physician Decision | 0 | 0 | 0 | 1 | 0 | 0 | 0 |
| Overall Study | Progression | 13 | 9 | 3 | 2 | 1 | 2 | 1 |
| Overall Study | Withdrawal by Subject | 0 | 1 | 0 | 0 | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | Total | ATC - Ipilimumab + Nivolumab | ATC - Ipilimumab Alone for Two Week | ATC - Nivolumab Alone for Two Week | MTC - Ipilimumab Alone for Two Weeks | DTC - Nivolumab Alone for Two Weeks | MTC - Nivolumab Alone for Two Week | DTC - Ipilimumab Alone for Two Weeks |
|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 62.1 Years STANDARD_DEVIATION 11.9 | 58.4 Years STANDARD_DEVIATION 8.3 | 69.3 Years STANDARD_DEVIATION 16.9 | 51.4 Years STANDARD_DEVIATION 2.1 | 51.8 Years STANDARD_DEVIATION 16.3 | 64.9 Years STANDARD_DEVIATION 11.8 | 54.7 Years STANDARD_DEVIATION 2.9 | 63.4 Years STANDARD_DEVIATION 10.3 |
| ECOG Performance Status 0 | 17 Participants | 1 Participants | 3 Participants | 0 Participants | 1 Participants | 6 Participants | 0 Participants | 6 Participants |
| ECOG Performance Status 1 | 31 Participants | 3 Participants | 3 Participants | 2 Participants | 3 Participants | 9 Participants | 3 Participants | 8 Participants |
| ECOG Performance Status 2 | 4 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 46 Participants | 4 Participants | 3 Participants | 2 Participants | 4 Participants | 16 Participants | 2 Participants | 15 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Asian | 25 Participants | 0 Participants | 3 Participants | 2 Participants | 4 Participants | 1 Participants | 0 Participants | 15 Participants |
| Race/Ethnicity, Customized Black or African American | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Other | 3 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized White | 20 Participants | 3 Participants | 0 Participants | 0 Participants | 0 Participants | 15 Participants | 2 Participants | 0 Participants |
| Sex: Female, Male Female | 25 Participants | 2 Participants | 4 Participants | 0 Participants | 2 Participants | 8 Participants | 2 Participants | 7 Participants |
| Sex: Female, Male Male | 24 Participants | 2 Participants | 0 Participants | 2 Participants | 2 Participants | 8 Participants | 1 Participants | 9 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk |
|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 5 / 16 | 5 / 16 | 1 / 3 | 0 / 4 | 1 / 2 | 2 / 4 | 1 / 4 |
| other Total, other adverse events | 16 / 16 | 16 / 16 | 3 / 3 | 4 / 4 | 2 / 2 | 4 / 4 | 4 / 4 |
| serious Total, serious adverse events | 5 / 16 | 3 / 16 | 1 / 3 | 0 / 4 | 2 / 2 | 2 / 4 | 0 / 4 |
Outcome results
Primary
Best Overall Response Rate
Best overall response rate is defined as the percentage of participants who achieved Complete response (CR) or partial response (PR) on treatment based on RECIST 1.1 criteria. Per RECIST 1.1 for target lesions: CR is complete disappearance of all target lesions and PR is at least a 30% decrease in the sum of longest diameter (LD) of target lesions, taking as reference baseline sum LD. PR or better overall response assumes at a minimum incomplete response/stable disease (SD) for the evaluation of non-target lesions and absence of new lesions.
Time frame: Median (range) treatment duration (days) of 163.0 (21.0-734.0) for DTC cohort, for MTC cohort was 58.0 (30.0-252.0), and for ATC cohort 135.5 (10.0-735.0).
Population: It was pre-specified in the Study Protocol to report data by disease cohort irrespective of assigned treatment sequence.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Differentiated Thyroid Cancer (Primary Cohort) | Best Overall Response Rate | 9.4 percentage of participants |
| Medullary Thyroid Cancer (Exploratory Cohort) | Best Overall Response Rate | 0 percentage of participants |
| Anaplastic Thyroid Cancer (Exploratory Cohort) | Best Overall Response Rate | 30 percentage of participants |
Secondary
Median Progression Free Survival
Progression-Free Survival (PFS) based on Kaplan-Meier methodology is defined as the time from randomization (or registration) to the earlier of progression or death due to any cause. Participants alive without disease progression are censored at date of last disease evaluation. Participants alive without PD were censored at the earliest of the date of the last disease evaluation or start of new anticancer therapy. Per RECIST 1.1 for target lesions: PD is at least a 20% increase in sum LD, taking as reference the smallest sum on study with at least 5 mm absolute increase. For non-target lesions, progression-free means no new lesions or unequivocal progression on existing non-target lesions or not evaluated.
Time frame: Median (range) follow-up (months) for DTC cohort was 24.0 (1.84 - 24.7), for MTC cohort was 24.0 (23.0-24.2), and for ATC cohort was 22.2 (0.46 - 26.1).
Population: It was pre-specified in the Study Protocol to report data by disease cohort irrespective of assigned treatment sequence.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Differentiated Thyroid Cancer (Primary Cohort) | Median Progression Free Survival | 7.11 Months |
| Medullary Thyroid Cancer (Exploratory Cohort) | Median Progression Free Survival | 2.14 Months |
| Anaplastic Thyroid Cancer (Exploratory Cohort) | Median Progression Free Survival | 4.29 Months |
Secondary
Overall Survival at 2 Years (OS2)
Overall Survival is the percent probability estimate at 2 years based on Kaplan-Meier methodology. OS is defined as the time from randomization (or registration) to death due to any cause, or censored at date last known alive.
Time frame: Median (range) follow-up (months) for DTC cohort was 24.0 (1.84 - 24.7), for MTC cohort was 24.0 (23.0-24.2), and for ATC cohort was 22.2 (0.46 - 26.1).
Population: It was pre-specified in the Study Protocol to report data by disease cohort irrespective of assigned treatment sequence.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Differentiated Thyroid Cancer (Primary Cohort) | Overall Survival at 2 Years (OS2) | 77.2 Percent Probability |
| Medullary Thyroid Cancer (Exploratory Cohort) | Overall Survival at 2 Years (OS2) | 85.7 Percent Probability |
| Anaplastic Thyroid Cancer (Exploratory Cohort) | Overall Survival at 2 Years (OS2) | 55.6 Percent Probability |
Secondary
Treatment-Related Adverse Events Rate
Treatment-related adverse events rate was defined as the proportion of participants who experienced an adverse event with treatment attribution of possible, probable or definite, including all grades based on the Common Toxicity Criteria for Adverse Events Version 4.0 (CTCAEv4) as reported on case report forms.
Time frame: AEs were assessed every two weeks on treatment and within 30 days after the last dose. Median (range) treatment duration (days) of 163.0 (21.0-734.0) for DTC cohort, for MTC cohort was 58.0 (30.0-252.0), and for ATC cohort 135.5 (10.0-735.0).
Population: It was pre-specified in the Study Protocol to report data by disease cohort irrespective of assigned treatment sequence.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Differentiated Thyroid Cancer (Primary Cohort) | Treatment-Related Adverse Events Rate | 0.81 proportion of participants |
| Medullary Thyroid Cancer (Exploratory Cohort) | Treatment-Related Adverse Events Rate | 1 proportion of participants |
| Anaplastic Thyroid Cancer (Exploratory Cohort) | Treatment-Related Adverse Events Rate | 0.80 proportion of participants |