Clinical Trials /

PDR001 Combination Therapy for Radioiodine-Refractory Thyroid Cancer

NCT04544111

Description:

The purpose of this study is to find out whether a drug called PDR001, combined with either trametinib or dabrafenib, is a safe and effective treatment for thyroid cancer.

Related Conditions:
  • Poorly Differentiated Thyroid Gland Carcinoma
  • Thyroid Gland Follicular Carcinoma
  • Thyroid Gland Papillary Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: PDR001 Combination Therapy for Radioiodine-Refractory Thyroid Cancer
  • Official Title: Phase II Study of PDR001 in Combination With MAPK Pathway Inhibitors in Patients With Radioiodine-Refractory Thyroid Cancer

Clinical Trial IDs

  • ORG STUDY ID: 20-258
  • NCT ID: NCT04544111

Conditions

  • Thyroid Cancer
  • Thyroid Cancer, Follicular
  • Papillary Thyroid Cancer
  • Follicular Thyroid Cancer
  • Hurthle Cell Tumor
  • Poorly Differentiated Thyroid Gland Carcinoma
  • Hurthle Cell Thyroid Neoplasia

Interventions

DrugSynonymsArms
TrametinibCohort A-BRAF WT tumors
DabrafenibCohort B-BRAF Mutant
PDR001Cohort A-BRAF WT tumors

Purpose

The purpose of this study is to find out whether a drug called PDR001, combined with either trametinib or dabrafenib, is a safe and effective treatment for thyroid cancer.

Trial Arms

NameTypeDescriptionInterventions
Cohort A-BRAF WT tumorsExperimentalCohort A (BRAF WT tumors): trametinib (T) 2mg by mouth daily plus PDR001 400mg IV every 4 weeks
  • Trametinib
  • PDR001
Cohort B-BRAF MutantExperimentalCohort B (BRAF Mutant, resistant to previous BRAF inhibitors): dabrafenib (D) 150 mg twice daily (OR at dose the patient previously tolerated) plus PDR001 400mg IV every 4 weeks.
  • Dabrafenib
  • PDR001

Eligibility Criteria

        Inclusion Criteria:

          -  Cohort A Only: Confirmation in a CLIA certified laboratory that one of the patient's
             thyroid tumors (primary tumor, recurrent tumor, or metastases) does not possess a
             BRAFV600- mutation (non-V600- BRAF mutations, including BRAF translocations, may be
             included in this cohort).

          -  Cohort B Only: Confirmation in a CLIA certified laboratory that one of the patient's
             thyroid tumors (primary tumor, recurrent tumor, or metastases) possesses a BRAFV600-
             mutation (e.g. V600E, V600K, V600D).

          -  Cohort B Only: Patients must have documented progression (evidence of tumor growth or
             appearance of new tumor) on prior BRAF directed therapy (e.g. (but not limited to)
             vemurafenib, dabrafenib) and must have tolerated this therapy without > Grade 3
             toxicity on their most recent evaluation (excluding Grade 4 asymptomatic laboratory
             abnormalities).

          -  Patients must have pathologically or cytologically confirmed differentiated thyroid
             cancer of follicular origin (including papillary thyroid carcinoma, follicular thyroid
             carcinoma, hurthle cell carcinomas, poorly differentiated thyroid carcinoma and their
             respective variants).

          -  Patients must have RECIST v1.1 measurable disease.

          -  Patients must have recurrent or metastatic disease not amenable to curative surgery or
             radiation.

          -  Age > 18 years.

          -  ECOG performance status of 0 or 1.

          -  Patients must have no recent treatment for thyroid cancer as defined as:

               -  No prior RAI therapy is allowed <6 months prior to initiation of therapy on this
                  protocol. A diagnostic study using <10 mCi of RAI is not considered RAI therapy

               -  No external beam radiation therapy <4weeks prior to initiation of therapy on this
                  protocol.

               -  No chemotherapy or targeted therapy (e.g., tyrosine kinase inhibitor) is allowed
                  <4 weeks prior to the initiation of therapy on this protocol (an exception to
                  this is patients on prior BRAF targeted therapy who will be enrolling into Cohort
                  B).

          -  Patients must be able to swallow and retain orally-administered pills without any
             clinically significant gastrointestinal abnormalities that may alter absorption, such
             as malabsorption syndrome or major resection of the stomach or bowels.

          -  Patients must have tissue from the primary tumor or metastases available for
             correlative studies. Either a paraffin block or at least 20 unstained slides are
             acceptable (30 unstained slides would be ideal). (If less than twenty unstained slides
             are available and a paraffin bloc is not available, the patient may be able to
             participate at the discretion of the investigator).

          -  Patients must agree to undergo two research biopsies of (a) malignant lesion(s). Tumor
             tissue obtained prior to study consent or treatment as part of standard of care can
             also be submitted in lieu of performance of the first pre-treatment biopsy if the
             Principal Investigator deems it to be of sufficient quantity/quality/timeliness.
             Patients may be exempt from biopsy if 1) the investigator or person performing the
             biopsy judges that no tumor is accessible for biopsy, 2) the investigator or person
             performing the biopsy feels that the biopsy poses too great of a risk to the patient,
             or 3) the patient cannot be safely removed from anti-coagulation therapy (if the
             anti-coagulation therapy needs to be temporarily held for the biopsy procedure). If
             the only tumor accessible for biopsy is also the only lesion that can be used for
             RECIST v1.1 response evaluation, then the patient may be exempt from biopsy. If the
             investigator deems a second research biopsy to be high risk after a patient has
             completed the first research biopsy, the patient may be exempt from the second biopsy.

          -  Screening laboratory values must meet the following criteria:

               -  WBC ≥ 2000/µl

               -  Neutrophils ≥ 1500/µl

               -  Platelets ≥ 100 x 10^3/µl

               -  Hemoglobin > 9.0 g/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)

               -  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

          -  Left ventricular ejection fraction ≥ institutional lower limit of normal by
             transthoracic echocardiogram (ECHO) performed within 1 month of study drug initiation.

        Exclusion Criteria:

          -  Cohort A Only:

               -  Patients with the following ophthalmological finding/conditions:

          -  Intraocular pressure >21 mmHg, or uncontrolled glaucoma (irrespective of intraocular
             pressure).

          -  Current or past history of central serous retinopathy or retinal vein occlusion.

          -  Cohort A Only: Prior therapy with a MEK 1/2 targeted drug (with the exception of
             patients who received this therapy for a defined period of time to enhance radioiodine
             activity).

          -  Symptomatic metastatic brain or leptomeningeal tumors (asymptomatic or treated
             metastatic brain or leptomeningeal tumors are allowed).

          -  Prior therapy directed at the PD1/PD-L1 axis.

          -  History or evidence of cardiovascular risk including any of the following:

               -  A QT interval corrected for heart rate using the Bazett's formula QTcB ≥ 480
                  msec.

               -  History or evidence of current clinically significant uncontrolled arrhythmias
                  (Exception: patients with controlled atrial fibrillation for >30 days prior to
                  randomization are eligible).

               -  History of acute coronary syndromes (including myocardial infarction and unstable
                  angina), coronary angioplasty, or stenting within 6 months prior to
                  randomization.

               -  History or evidence of current ≥ Class II congestive heart failure as defined by
                  the New York Heart Association (NYHA) functional classification system.

               -  Treatment-refractory hypertension defined as a blood pressure of systolic >140
                  mmHg and/or diastolic >90 mmHg which cannot be controlled by anti-hypertensive
                  therapy.

          -  Prior malignancy if diagnosed and treated within 2 years of trial drug initiation
             (with the exception of non-melanoma skin cancers). Patients may be included if they
             have completed therapy for a prior malignancy >2 years prior to drug initiation and
             are currently NED.

          -  Use of any live vaccines against infectious diseases within 4 weeks of initiation of
             study treatment.

          -  Systemic chronic steroid therapy (≥ 10mg/day prednisone or equivalent) or any
             immunosuppressive therapy (including but not limited to methotrexate, azathioprine,
             and TNF-alpha blockers) 7 days prior to planned first date of study treatment (note:
             topical, inhaled, nasal, intra-articular and ophthalmic steroids are allowed).

          -  Active, known or suspected autoimmune disease or documented history of autoimmune
             disease with the exception of vitiligo, controlled type I diabetes mellitus on stable
             insulin, autoimmune thyroid disease or psoriasis not requiring systemic treatment.

          -  Allogenic bone marrow or solid organ transplant.

          -  History of severe hypersensitivity reactions to monoclonal antibodies or any other
             study drug components which in the opinion of the investigator may pose an increased
             risk of serious infusion reaction.

          -  Known history of current interstitial lung disease or non-infectious pneumonitis.

          -  Patients with active hepatitis B infection (HBV surface antigen positive).

          -  Subject is known to be positive for Human Immunodeficiency Virus (HIV) or active
             Hepatitis C Virus (HCV). Testing for HIV or Hepatitis C prior to initiation of the
             study drug is not required. If a patient has a known history of treated HCV, then a
             viral load is required to confirm clearance of infection.

          -  Pregnant or nursing (lactating) women confirmed by a positive hCG laboratory test
             within 72 hours prior to initiating study treatment.

          -  Women of child-bearing potential (as defined in Appendix 18.3), unless they are using
             highly effective methods of contraception during dosing and for 150-days after
             stopping treatment with PDR001. Highly effective contraception methods include:

               -  Total abstinence (when this is in line with the preferred and usual lifestyle of
                  the patient). Periodic abstinence (e.g., calendar, ovulation, symptothermal,
                  post-ovulation methods) and withdrawal are not acceptable methods of
                  contraception

               -  Female sterilization (have had surgical bilateral oophorectomy with or without
                  hysterectomy), total hysterectomy, or tubal ligation at least six weeks before
                  taking study treatment. In case of oophorectomy alone, only when the reproductive
                  status of the woman has been confirmed by follow up hormone level assessment

               -  Male sterilization (at least 6 months prior to screening). The vasectomized male
                  partner should be the sole partner for that patient

               -  Use of oral, injected or implanted hormonal methods of contraception or placement
                  of an intrauterine device (IUD) or intrauterine system (IUS), or other forms of
                  hormonal contraception that have comparable efficacy (failure rate <1%), for
                  example hormone vaginal ring or transdermal hormone contraception. NOTE: In case
                  of use of oral contraception women should have been stable on the same pill for a
                  minimum of 3 months before taking study treatment.

               -  Women are considered post-menopausal and not of child bearing potential if they
                  have had 12 months of natural (spontaneous) amenorrhea with an appropriate
                  clinical profile (i.e. age appropriate, history of vasomotor symptoms) or have
                  had surgical bilateral oophorectomy (with or without hysterectomy), total
                  hysterectomy, or tubal ligation at least six weeks ago. In the case of
                  oophorectomy alone, only when the reproductive status of the woman has been
                  confirmed by follow up hormone level assessment is she considered not of child
                  bearing potential.

          -  Sexually active males unless they use a condom during intercourse while on treatment
             and for 150 days after stopping treatment with PDR001 and should not father a child in
             this period. A condom is required to be used by vasectomized men as well during
             intercourse to prevent delivery of the drug via semen.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Overall response rate
Time Frame:1 year
Safety Issue:
Description:The primary endpoint is to determine the overall response rate (ORR=CR+PR) as documented by RECIST v1.1 criteria within each cohort.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Memorial Sloan Kettering Cancer Center

Trial Keywords

  • Thyroid Cancer
  • PDR001
  • Radioiodine-Refractory Thyroid Cancer
  • Memorial Sloan Kettering Cancer Center
  • 20-258

Last Updated

September 3, 2020