Clinical Trials /

Dabrafenib, Trametinib, and Spartalizumab for the Treatment of BRAF V600E or V600K Mutation Positive Stage IIIB/C/D Melanoma

NCT04310397

Description:

This phase II trial studies how well dabrafenib, trametinib, and spartalizumab works in treating patients with BRAF V600E or V600K mutation positive stage IIIB/C/D melanoma, who do not achieve a pathologic complete response after 8 weeks of dabrafenib and trametinib treatment. Patients who achieve a pathologic complete response after 8 weeks of neoadjuvant dabrafenib and trametinib will receive adjuvant dabrafenib and trametinib. Dabrafenib and trametinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Immunotherapy with monoclonal antibodies, such as spartalizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving dabrafenib, trametinib, and spartalizumab may help to control melanoma.

Related Conditions:
  • Melanoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Dabrafenib, Trametinib, and Spartalizumab for the Treatment of BRAF V600E or V600K Mutation Positive Stage IIIB/C/D Melanoma
  • Official Title: Altering Adjuvant Therapy Based on Pathologic Response to Neoadjuvant Dabrafenib and Trametinib (ALTER-PATH NeoDT)

Clinical Trial IDs

  • ORG STUDY ID: 2019-0906
  • SECONDARY ID: NCI-2020-00941
  • SECONDARY ID: 2019-0906
  • SECONDARY ID: P30CA016672
  • NCT ID: NCT04310397

Conditions

  • Pathologic Stage IIIB Cutaneous Melanoma AJCC v8
  • Pathologic Stage IIIC Cutaneous Melanoma AJCC v8
  • Pathologic Stage IIID Cutaneous Melanoma AJCC v8

Interventions

DrugSynonymsArms
DabrafenibBRAF Inhibitor GSK2118436, GSK-2118436, GSK-2118436A, GSK2118436Treatment (dabrafenib, trametinib, surgery, spartalizumab)
SpartalizumabPDR-001, PDR001Treatment (dabrafenib, trametinib, surgery, spartalizumab)
TrametinibGSK1120212, JTP-74057, MEK Inhibitor GSK1120212, MekinistTreatment (dabrafenib, trametinib, surgery, spartalizumab)

Purpose

This phase II trial studies how well dabrafenib, trametinib, and spartalizumab works in treating patients with BRAF V600E or V600K mutation positive stage IIIB/C/D melanoma, who do not achieve a pathologic complete response after 8 weeks of dabrafenib and trametinib treatment. Patients who achieve a pathologic complete response after 8 weeks of neoadjuvant dabrafenib and trametinib will receive adjuvant dabrafenib and trametinib. Dabrafenib and trametinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Immunotherapy with monoclonal antibodies, such as spartalizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving dabrafenib, trametinib, and spartalizumab may help to control melanoma.

Detailed Description

      PRIMARY OBJECTIVE:

      I. To determine the 12-month relapse free survival (RFS) rate in stage IIIB/C/D melanoma
      patients who, after 8 weeks of neoadjuvant dabrafenib and trametinib, do not achieve a
      pathologic complete response (pCR) and receive adjuvant dabrafenib, trametinib and
      spartalizumab.

      SECONDARY OBJECTIVES:

      I. To evaluate the safety of neoadjuvant dabrafenib and trametinib and adjuvant dabrafenib,
      trametinib and spartalizumab.

      II. To determine the 12-month relapse free survival (RFS) rate in stage IIIB/C/D.

      III. Melanoma patients who, after 8 weeks of neoadjuvant dabrafenib and trametinib, achieve a
      pCR and receive adjuvant dabrafenib and trametinib.

      IV. To assess the recurrence patterns, distant metastasis-free survival (DMFS), and overall
      survival (OS) in all patients treated on protocol.

      EXPLORATORY OBJECTIVES:

      I. To assess immunological and molecular features of treatment response and resistance.

      II. To assess circulating markers and correlate them with treatment response and relapse and
      toxicity III. To assess the impact of neoadjuvant therapy on surgical resectability.

      OUTLINE:

      NEOADJUVANT TREATMENT: Patients receive dabrafenib orally (PO) twice daily (BID) and
      trametinib PO once daily (QD) on days 1-28. Treatment repeats every 28 days for 2 cycles in
      the absence of disease progression or unacceptable toxicity.

      SURGERY: Patients undergo surgical resection of melanoma.

      ADJUVANT TREATMENT OF pCR PATIENTS: Patients receive dabrafenib PO BID and trametinib PO QD
      on days 1-28. Cycles repeats every 28 days for 44 weeks in the absence of disease progression
      or unacceptable toxicity.

      ADJUVANT TREATMENT OF NON pCR PATIENTS: Patients receive spartalizumab intravenously (IV)
      over 30 minutes on day 1, dabrafenib PO BID and trametinib PO QD on days 1-28. Cycles repeats
      every 28 days for 44 weeks in the absence of disease progression or unacceptable toxicity.

      After completion of study treatment, patients are followed up every 3-4 months for 2 years.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (dabrafenib, trametinib, surgery, spartalizumab)ExperimentalNEOADJUVANT TREATMENT: Patients receive dabrafenib PO BID and trametinib PO QD on days 1-28. Treatment repeats every 28 days for 2 cycles in the absence of disease progression or unacceptable toxicity. SURGERY: Patients undergo surgical resection of melanoma. ADJUVANT TREATMENT OF pCR PATIENTS: Patients receive dabrafenib PO BID and trametinib PO QD on days 1-28. Cycles repeats every 28 days for 44 weeks in the absence of disease progression or unacceptable toxicity. ADJUVANT TREATMENT OF NON pCR PATIENTS: Patients receive spartalizumab IV over 30 minutes on day 1, dabrafenib PO BID and trametinib PO QD on days 1-28. Cycles repeats every 28 days for 44 weeks in the absence of disease progression or unacceptable toxicity.
  • Dabrafenib
  • Spartalizumab
  • Trametinib

Eligibility Criteria

        Inclusion Criteria:

          -  Capable of giving written informed consent, which includes compliance with the
             requirements and restrictions listed in the consent form

          -  Patients must have histologically or cytologically confirmed clinically detected, node
             involved Stage IIIB/C/D melanoma by American Joint Committee on Cancer (AJCC) version
             8 and surgically resectable disease. The definition of resectability can be determined
             by the patient's surgical oncologist and verified via discussion at multidisciplinary
             tumor conference attended by melanoma medical and surgical oncology staff. Resectable
             tumors are defined as having no significant vascular, neural or bony involvement that
             would preclude complete resection or necessitate the use of adjuvant radiation. Only
             cases where a complete surgical resection with tumor- free margins can safely be
             achieved are defined as resectable

          -  BRAF mutation-positive melanoma (V600E or V600K) based on report from a Clinical
             Laboratory Improvement Act (CLIA) certified laboratory

          -  Patients must have measurable disease, defined by Response Evaluation Criteria in
             Solid Tumors (RECIST) 1.1

          -  Patients who have been previously treated in the adjuvant setting with ipilimumab or
             interferon alpha or investigational vaccines for melanoma will be eligible for
             treatment after a 28 day wash-out period

          -  Patients who have previously received anti PD-1 in the adjuvant setting will be
             allowed if it has been six months or longer since previous drug exposure

          -  Eastern Cooperative Oncology Group (ECOG) performance status 0-1

          -  Women of childbearing potential, defined as all women physiologically capable of
             becoming pregnant will be required to use highly effective methods of contraception
             during dosing and for 150-days after stopping treatment with spartalizumab. Highly
             effective contraception methods include:

               -  Total abstinence (when this is in line with the preferred and usual lifestyle of
                  the subject). 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 subject

               -  Placement of a non-hormonal intrauterine device (IUD) or intrauterine system
                  (IUS) with a documented failure rate of less than 1% per year

               -  Notes:

                    -  Double-barrier contraception: condom and occlusive cap (diaphragm or
                       cervical/vault caps) with a vaginal spermicidal agent
                       (foam/gel/cream/suppository) are not considered highly effective methods of
                       contraception.

                    -  Hormonal-based methods (e.g., oral contraceptives) are not considered as
                       highly effective methods of contraception due to potential drug-drug
                       interactions with dabrafenib.

          -  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 childbearing potential

          -  Sexually active males must use a condom during intercourse while on treatment and for
             150 days after stopping treatment with spartalizumab and should not father a child in
             this period. A condom is required to be used by vasectomized men as well during
             intercourse in order to prevent delivery of the drug via semen

          -  Absolute neutrophil count (ANC) >= 1500/uL

          -  Platelets >= 100,000/uL

          -  Hemoglobin >= 9.0 g/dL or >= 5.6 mmol/L

               -  Criteria must be met without erythropoietin dependency and without packed red
                  blood cell (pRBC) transfusion within last 2 weeks

          -  Creatinine =< 1.5 x upper limit of normal (ULN) OR measured or calculated creatinine
             clearance (glomerular filtration rate [GFR] can also be used in place of creatinine or
             creatinine clearance [CrCl]) >= 30 mL/min for participant with creatinine levels > 1.5
             x institutional ULN

          -  Total bilirubin =< 1.5 x ULN OR direct bilirubin =< ULN for participants with total
             bilirubin levels > 1.5 x ULN

          -  Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and
             alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) =< 2.5 x
             ULN

          -  International normalized ratio (INR) OR prothrombin time (PT) =<1.5 x ULN unless
             participant is receiving anticoagulant therapy as long as prothrombin time (PT) or
             partial thromboplastin time (aPTT) is within therapeutic range of intended use of
             anticoagulants

          -  Activated partial thromboplastin time (aPTT) =< 1.5 x ULN unless participant is
             receiving anticoagulant therapy as long as PT or aPTT is within therapeutic range of
             intended use of anticoagulants

        Exclusion Criteria:

          -  Currently receiving cancer therapy (chemotherapy, radiation therapy, immunotherapy, or
             biologic therapy) or investigational anti-cancer drug within 28 days

          -  Evidence of metastatic melanoma or patients with only in-transit metastases without
             involved nodes

          -  Prior BRAF or MEK inhibitor use

          -  Prior anti PD-1 or anti PD-L1 inhibitor use in last 6 months

          -  Prior malignancy active within the previous 2 years except for patient's prior
             diagnosis of melanoma and locally curable cancers that have been apparently cured,
             such as basal or squamous cell skin cancer, superficial bladder cancer, or carcinoma
             in situ of the prostate, cervix, or breast with local control measures (surgery,
             radiation)

          -  Subjects with active, known or suspected autoimmune disease. Subjects with 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 are permitted
             to enroll

          -  Subjects with 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

          -  Any positive test result for hepatitis B or C and human immunodeficiency virus (HIV)
             virus indicating acute or chronic infection

          -  Known history of testing positive for human immunodeficiency virus or known acquired
             immunodeficiency syndrome

          -  History of severe hypersensitivity reaction to any monoclonal antibody

          -  History of Central serous retinopathy (CSR) or retinal vein occlusion (RVO), or
             predisposing factors to RVO or CSR (e.g. uncontrolled glaucoma or ocular hypertension,
             uncontrolled systemic disease such as hypertension, diabetes mellitus, or history of
             hyperviscosity or hypercoagulability syndromes)

          -  Presence of active gastrointestinal disease or other condition that will interfere
             significantly with the absorption, distribution, metabolism, or excretion of drugs

          -  Corrected QT (QTc) interval >= 480 msec (>= 500 msec for subjects with bundle branch
             block)

          -  Uncontrolled arrhythmias

          -  Class II, III, or IV heart failure as defined by the New York Heart Association (NYHA)
             functional classification system

          -  Pregnant or lactating female

          -  Unwillingness or inability to follow the procedures required in the protocol

          -  Uncontrolled diabetes, hypertension or other medical conditions that may interfere
             with assessment of toxicity

          -  Subjects with known glucose 6 phosphate dehydrogenase (G6PD) deficiency
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Relapse-free survival (RFS) rate
Time Frame:up to 12 months
Safety Issue:
Description:Will be estimated with a 95% confidence interval by using the Kaplan-Meier method.

Secondary Outcome Measures

Measure:Incidence of adverse events
Time Frame:Up to 2 years
Safety Issue:
Description:The rate of grade 3+ adverse events will be tabulated and presented by group.
Measure:Overall survival
Time Frame:up to 2 years
Safety Issue:
Description:Will be reported with 95% confidence intervals, and Cox regression models will be used to assess the association between similar covariates.
Measure:Distant metastasis-free survival
Time Frame:up to 2 years
Safety Issue:
Description:Will be reported with 95% confidence intervals, and Cox regression models will be used to assess the association between similar covariates.

Details

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

Trial Keywords

  • Melanoma
  • Neoadjuvant
  • Pathological Response
  • Targeted Therapy
  • Immunotherapy

Last Updated

March 13, 2020