Clinical Trials /

A Study of Alectinib in RET-rearranged Non-small Cell Lung Cancer or RET-mutated Thyroid Cancer

NCT03131206

Description:

This research trial is studying a drug called alectinib as a possible treatment for non-small cell lung cancer (NSCLC) with specific genetic alterations known as ALK or RET rearrangements, and thyroid cancer with RET rearrangements.

Related Conditions:
  • Non-Small Cell Lung Carcinoma
  • Thyroid Gland Carcinoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: A Study of Alectinib in RET-rearranged Non-small Cell Lung Cancer or RET-mutated Thyroid Cancer
  • Official Title: A Phase 1/2 Study of Alectinib in RET-rearranged Non-small Cell Lung Cancer or RET-mutated Thyroid Cancer

Clinical Trial IDs

  • ORG STUDY ID: 17-080
  • NCT ID: NCT03131206

Conditions

  • ALK-positive Non-small Cell Lung Cancer (NSCLC)
  • RET-positive Non-small Cell Lung Cancer (NSCLC)
  • RET-positive Thyroid Cancer

Interventions

DrugSynonymsArms
AlectinibAlecensaPhase 1 RP2D of alectinib

Purpose

This research trial is studying a drug called alectinib as a possible treatment for non-small cell lung cancer (NSCLC) with specific genetic alterations known as ALK or RET rearrangements, and thyroid cancer with RET rearrangements.

Detailed Description

      This is a Phase I/II research study, which means that researchers are testing different doses
      of the drug alectinib in participants with cancer to evaluate its safety, determine a safe
      dosage range, and identify side effects.

      The FDA (the U.S. Food and Drug Administration) has approved alectinib as a treatment option
      for NSCLC, but at a different dosage.

      There are two parts to this study, Phase 1 and Phase 2. In Phase 1, patients with ALK or RET
      rearranged NSCLC will receive different doses of alectinib to determine the highest dose that
      can be administered without severe or unmanageable side effects. This is called the maximum
      tolerated dose and will be the recommended dose for the next part of the study, Phase 2. A
      Phase I clinical trial tests the safety of an investigational drug and also tries to define
      the appropriate dose of the investigational drug to use for further studies.
      "Investigational" means that the drug is being studied.

      During Phase 2, participants with RET rearranged NSCLC or thyroid cancer will be given the
      maximum tolerated dose. During both Phase 1 and Phase 2, the investigators will determine the
      effect alectinib has on the body, and the effect alectinib has on cancer.

      Alectinib belongs to a class of drugs known as tyrosine kinase inhibitors, which stop
      tyrosine kinases from working. Tyrosine kinases are enzymes that are responsible for
      activating many proteins in the body's cells. The ALK and RET kinases play an important role
      in the survival and growth of tumor cells and in the ability of tumor cells to spread to
      different parts of the body. In laboratory studies and in patients, alectinib has been shown
      to block the ALK and RET kinases. By blocking these kinases and stopping them from working,
      it is hoped that alectinib may prevent the survival of tumor cells in addition to stopping
      their growth and ability to spread.

      The purpose of this research study is to learn about the effects of the study drug alectinib,
      and to find the best dose for treating ALK-positive or RET-positive cancers.
    

Trial Arms

NameTypeDescriptionInterventions
Phase 1 RP2D of alectinibExperimentalThe investigators are looking for the highest dose of the study drug that can be administered safely without severe or unmanageable side effects in participants that have NSCLC, not everyone who participates in this research study will receive the same dose of the study drug. The dosage will depend on the number of participants who have been enrolled in the study and how well the dosage has been tolerated. Alectinib Oral, BID A 7-day lead-in dosing period will be administered at the start of each dose level. Each treatment cycle will be defined as 28 consecutive days.
  • Alectinib
Cohort AExperimentalParticipants with RET-rearranged NSCLC with no previous history of RET-TKI therapy. Alectinib Oral, BID, participants will receive the RP2D identified during Phase 1. Each treatment cycle will be defined as 28 consecutive days.
  • Alectinib
Cohort BExperimentalParticipants with RET-rearranged NSCLC with previous history of RET-TKI therapy. Alectinib Oral, BID, participants will receive the RP2D identified during Phase 1. Each treatment cycle will be defined as 28 consecutive days.
  • Alectinib
Cohort CExperimentalParticipants with RET-rearranged thyroid cancer Alectinib Oral, BID, participants will receive the RP2D identified during Phase 1. Each treatment cycle will be defined as 28 consecutive days.
  • Alectinib

Eligibility Criteria

        Inclusion Criteria:

          -  Tumor Types:

               -  Phase 1: Subjects must have a histologically or cytologically confirmed diagnosis
                  of locally advanced (AJCC Stage IIIB) not amenable to curative therapy or
                  metastatic (AJCC Stage IV) NSCLC that carries a RET rearrangement, as determined
                  by fluorescence in situ hybridization (FISH), reverse transcription polymerase
                  chain reaction (RT-PCR), or next generation sequencing (NGS) via a CLIA-certified
                  local diagnostic test (LDT).

                  --- OR-

               -  Phase 1: Subjects must have a histologically or cytologically confirmed diagnosis
                  of metastatic (AJCC Stage IV) NSCLC that carries an ALK rearrangement with CNS
                  metastases, as determined by FISH, RT-PCR, immunohistochemistry (IHC), or NGS via
                  a CLIA-certified LDT.

               -  Phase 2 Cohorts A&B: Subjects must have a histologically or cytologically
                  confirmed diagnosis of locally advanced (AJCC Stage IIIB) not amenable to
                  curative therapy or metastatic (AJCC Stage IV) NSCLC that carries a RET
                  rearrangement, as determined by FISH, RT-PCR, or NGS via a CLIA-certified LDT.

               -  Phase 2 Cohort C (thyroid cancer): Subjects must have a histologically or
                  cytologically confirmed diagnosis of metastatic thyroid cancer (Stage IV) that
                  carries either a RET rearrangement or activating RET mutation, as determined by
                  FISH, RT-PCR, or NGS via a CLIA-certified LDT.

          -  Disease Status Requirements:

               -  Phase 1: Subjects with a RET rearrangement must have had disease progression
                  after at least one prior line of systemic therapy. Subjects with an ALK
                  rearrangement may be either treatment naive or may have received prior treatment,
                  and must have CNS disease present at baseline. Subjects cannot have received more
                  than one prior RET TKI (such as, but not limited to, vandetanib, sorafenib,
                  sunitinib, ponatinib, or cabozantinib). Subjects enrolling to the Phase 1 portion
                  of the trial must not have received prior alectinib therapy.

               -  Phase 2:

                    -  Cohort A: RET-positive NSCLC subjects must have received at least one prior
                       line of therapy, but must be RET TKI-naive.

                    -  Cohort B: RET-positive NSCLC that has previously been treated with one RET
                       TKI. Subjects cannot have received more than one prior RET TKI and must not
                       have received prior alectinib.

                    -  Cohort C: RET-positive thyroid cancer, must be radioactive iodine
                       refractory.

          -  Subjects must have at least one measurable target lesion according to RECIST v1.1.

          -  Subjects enrolling to the phase 1 portion of the trial who have received a prior RET
             TKI must be able and willing to undergo a pre-treatment fresh tumor biopsy.

          -  Subjects enrolling to Cohort B or C of the phase 2 portion of the trial who have
             received a prior RET TKI must be able and willing to undergo a pre-treatment fresh
             tumor biopsy.

          -  All subjects must have archival tissue confirmed as available for enrollment. Subjects
             who are TKI naive who do not have archival tissue may undergo a fresh tumor biopsy in
             lieu of the archival tissue requirement. The archival tissue requirement may be waived
             for subjects after discussion with the principal investigator.

          -  Age ≥ 18 years.

          -  ECOG performance status ≤2 (See APPENDIX A)

          -  Subjects must have normal organ and marrow function as defined below:

        Adequate hematologic function

          -  Absolute neutrophil count ≥1,500/mcL

          -  Platelets ≥100,000/mcL

          -  Hemoglobin ≥ 9.0 g/dL -- Adequate renal function

          -  serum creatinine ≤1.5 x institutional ULN

             ---- OR-

          -  Estimated glomerular filtration rate (eGFR) ≥45 mL/min/1.73 m2 as calculated using the
             Modification of Diet Renal Disease Equation (See APPENDIX B)

               -  Subjects must have recovered from treatment toxicities to ≤ Grade 1 or to their
                  pretreatment levels. Subjects who have developed interstitial lung disease (ILD)
                  must have fully recovered.

               -  For all females of childbearing potential, a negative serum pregnancy test must
                  be obtained within 3 days prior to starting study treatment.

               -  For women who are not postmenopausal (≥12 months of non-therapy-induced
                  amenorrhea) or surgically sterile (absence of ovaries and/or uterus): agreement
                  to remain abstinent or use single or combined contraceptive methods that result
                  in a failure rate of < 1% per year during the treatment period and for at least 3
                  months after the last dose of study drug. Abstinence is only acceptable if it is
                  in line with the preferred and usual lifestyle of the subject. Periodic
                  abstinence (e.g., calendar, ovulation, symptothermal or postovulation methods)
                  and withdrawal are not acceptable methods of contraception. Examples of
                  contraceptive methods with a failure rate of < 1% per year include tubal
                  ligation, male sterilization, hormonal implants, established, proper use of
                  combined oral or injected hormonal contraceptives, and certain intrauterine
                  devices.

               -  For men: agreement to remain abstinent or use a contraceptive method that results
                  in a failure rate of < 1% per year during the treatment period and for at least 3
                  months after the last dose of study drug. Abstinence is only acceptable if it is
                  in line with the preferred and usual lifestyle of the subject. Periodic
                  abstinence (e.g., calendar, ovulation, symptothermal or postovulation methods)
                  and withdrawal are not acceptable methods of contraception.

               -  Ability to understand and the willingness to sign a written informed consent
                  document.

        Exclusion Criteria:

          -  Cytotoxic chemotherapy or immunotherapy within 3 weeks of study entry.

          -  Oral targeted therapy within 5 half-lives (if known) or 3 weeks (if half-life is
             unknown) of study entry.

          -  Phase 1: subjects who have received prior alectinib therapy.

          -  For enrollment to the phase 1 portion of the trial: Administration of any cytochrome
             P450 (CYP)3A inhibitors or inducers within 14 days prior to the first dose of
             alectinib and from Cycle 1 Day 1 - Cycle 2 Day 8 of the phase 1 portion of the trial.
             Following completion of this period, strong/potent cytochrome P450 (CYP)3A inhibitors
             or inducers are prohibited while on study. Please see APPENDIX C.

          -  Radiation therapy (except palliative to relieve bone pain) within 2 weeks of study
             entry. Palliative radiation (≤10 fractions) must have been completed at least 48 hours
             prior to study entry. Stereotactic or small field brain irradiation must have
             completed at least 2 weeks prior to study entry. Whole brain radiation must have
             completed at least 4 weeks prior to study entry.

          -  Major surgery within 4 weeks of study entry. Minor surgical procedures (e.g., port
             insertion) are not excluded, but sufficient time should have passed for wound healing
             (as determined by the treating investigator).

          -  Subjects who are receiving any other investigational agents.

          -  Liver disease characterized by:

             -- ALT or AST > 3 × institutional ULN (≥ 5 × ULN for subjects with concurrent liver
             metastasis) confirmed on two consecutive measurements

             --- OR-

          -  Absolute impaired excretory function (e.g., hyperbilirubinemia) or synthetic function
             or other conditions of decompensated liver disease such as coagulopathy, hepatic
             encephalopathy, hypoalbuminemia, ascites, and bleeding from esophageal varices

             --- OR-

          -  Impaired excretory function (e.g., hyperbilirubinemia) or synthetic function or other
             conditions of decompensated liver disease such as coagulopathy, hepatic
             encephalopathy, hypoalbuminemia, ascites, and bleeding from esophageal varices

             ---OR-

          -  Acute viral or active autoimmune, alcoholic, or other types of acute hepatitis

          -  Subjects with symptomatic CNS metastases who are neurologically unstable and/or
             require an increased dose of steroid to manage CNS symptoms within 1 week prior to the
             first day of treatment are excluded.

               -  Subjects with brain or leptomeningeal metastases that do not meet the above
                  criteria are allowed.

               -  Symptomatic disease is allowed as long as symptoms are controlled and stable.

          -  History of hypersensitivity to any of the additives in the alectinib drug formulation.

          -  Subjects with symptomatic bradycardia.

          -  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.

          -  Pregnant or breastfeeding women.

          -  Any GI disorder that may affect absorption of oral medications in the opinion of the
             treating investigator, such as malabsorption syndrome or major bowel or stomach
             resection.

          -  Subjects who are unable to swallow pills.

          -  Subjects with a history of a second primary malignancy. Exceptions include: subjects
             with a history of malignancies that were treated curatively and have not recurred
             within 3 years prior to study entry; resected basal and squamous cell carcinomas of
             the skin, and completely resected carcinoma in situ of any type.

          -  NCI-CTCAE v4.03 Grade 3 or higher toxicities due to any prior therapy (excluding
             alopecia), which have not shown improvement and are strictly considered to interfere
             with current study medication.

          -  Known HIV positivity or AIDS-related illness.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum Tolerated Dose (Phase 1)
Time Frame:28 Days
Safety Issue:
Description:Graded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03

Secondary Outcome Measures

Measure:Area under the plasma concentration versus time curve (AUC) of alectinib
Time Frame:4 months
Safety Issue:
Description:AUC pharmacokinetic parameters will be estimated using non-compartmental models. Comparisons across dose levels will be made to assess proportionality.
Measure:Progression Free Survival
Time Frame:2 Years
Safety Issue:
Description:RECIST 1.1 Criteria
Measure:Overall Survival
Time Frame:2 Years
Safety Issue:
Description:RECIST 1.1 Criteria
Measure:Duration of Response
Time Frame:2 Years
Safety Issue:
Description:RECIST 1.1 Criteria
Measure:Peak plasma concentration (Cmax) of alectinib
Time Frame:4 months
Safety Issue:
Description:Cmax pharmacokinetic parameters will be estimated using non-compartmental models. Comparisons across dose levels will be made to assess proportionality.

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Active, not recruiting
Lead Sponsor:Dana-Farber Cancer Institute

Trial Keywords

  • Non-small cell lung cancer
  • NSCLC
  • ALK
  • RET
  • alectinib
  • Thyroid cancer

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