Clinical Trials /

Study of CDX-3379, a Human Monoclonal Antibody Targeting ERBB3, in Combination With the MEK Inhibitor, Trametinib, in Patients With Advanced Stage NRAS Mutant and BRAF/NRAS Wildtype (WT) Melanoma

NCT03580382

Description:

The main goal of this study is to test if it is safe and effective to give CDX-3379 together to treat advanced melanoma in patients with the NRAS mutation and BRAF/NRAS wildtype.

Related Conditions:
  • Melanoma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Study of CDX-3379, a Human Monoclonal Antibody Targeting ERBB3, in Combination With the MEK Inhibitor, Trametinib, in Patients With Advanced Stage NRAS Mutant and BRAF/NRAS Wildtype (WT) Melanoma
  • Official Title: Study of CDX-3379, a Human Monoclonal Antibody Targeting ERBB3, in Combination With the MEK Inhibitor, Trametinib, in Patients With Advanced Stage NRAS Mutant and BRAF/NRAS Wildtype (WT) Melanoma

Clinical Trial IDs

  • ORG STUDY ID: 17-00363
  • NCT ID: NCT03580382

Conditions

  • Melanoma

Interventions

DrugSynonymsArms
Trametinib daily Until PDNRAS mutant melanoma
CDX-3379 (ERBB3 antibody)NRAS mutant melanoma

Purpose

The main goal of this study is to test if it is safe and effective to give CDX-3379 together to treat advanced melanoma in patients with the NRAS mutation and BRAF/NRAS wildtype.

Detailed Description

      Primary Objectives:

      Phase 1b: To determine the RP2D and assess the toxicity and tolerability of the combination
      of CDX-3379 (ERBB3 antibody) and trametinib (MEK inhibitor) in NRAS and BRAF/NRAS WT melanoma
      patients

      Phase 2: To estimate the response rates and duration of response of the combination of
      CDX-3379 (ERBB3 antibody) and trametinib in NRAS positive and BRAF/NRAS WT melanoma patients

      Secondary/Exploratory Objectives:

      Phase 1b: To assess clinical activity and steady-state pharmacokinetics of CDX-3379 and
      trametinib Phase 2: To compare the efficacy of the combination of CDX-3379 (ERBB3 antibody)
      and trametinib is more effective than a MEK inhibitor alone in NRAS positive and BRAF/NRAS WT
      melanoma patients alone using locally assessed progression free survival (PFS) and overall
      survival (OS).
    

Trial Arms

NameTypeDescriptionInterventions
NRAS mutant melanomaExperimentalC1D1-C1D21, CDX-3379 D1Trametinib daily Biopsy (days 14-16)
  • Trametinib daily Until PD
  • CDX-3379 (ERBB3 antibody)
WT melanomaExperimentalC1D1-C1D21, CDX-3379 D1Trametinib daily Biopsy (days 14-16)
  • Trametinib daily Until PD
  • CDX-3379 (ERBB3 antibody)

Eligibility Criteria

        Inclusion Criteria:

          -  1. Read, understood, and provided written informed consent and, if applicable, Health
             Insurance Portability and Accountability Act (HIPAA) authorization after the nature of
             the study has been fully explained and must be willing to comply with all study
             requirements and procedures.

             2. Male or female patients who are 18 years of age or older. 3. Patients with a
             diagnosis of histologically confirmed advanced (defined as unresectable stage III or
             IV) melanoma with the NRAS Q61 mutation or BRAF/NRAS WT for which there is no
             remaining standard therapy with curative potential or patients are ineligible or
             unable to tolerate therapy with curative potential.

               -  Any standard of care mutation testing is acceptable to document mutation status.

                  4.Patients must have archival tissue and at least one disease site amenable to
                  biopsy:

               -  For phase Ib, all patients will undergo fresh tumor biopsy

               -  For phase II, five patients with NRAS mutation and five patients with BRAF/NRAS
                  WT melanoma will undergo fresh tumor biopsy 5.Measurable (target) disease by
                  Response Evaluation Criteria In Solid Tumors (RECIST 1.1) criteria. Target
                  lesions selected for tumor measurements should be those where additional (eg
                  palliative) treatments are not indicated or anticipated.

               -  Measurable disease per RECIST 1.1 requirements: defined as longest diameter to be
                  recorded for non-nodal lesions > 10mm and short axis for nodal lesions >15 mm
                  using conventional techniques 6.All residual toxicity related to prior
                  radiotherapy or anticancer therapies (excluding alopecia, grade 2 fatigue,
                  vitiligo or endocrinopathies on stable replacement therapy) must resolve to grade
                  1 severity or less (or returned to baseline) prior to receipt of study treatment.

                  7.Adequate electrolytes, liver, renal, and hematology function as defined below:

                  a.Hemoglobin ≥ 9 g/dL b.Absolute neutrophil count ≥ 1500/mm3 c.Platelet count ≥
                  100,000/mm3 d.Aspartate aminotransferase (AST) and alanine aminotransferase (ALT)
                  ≤ 2.5 × upper limit of normal (ULN) (≤ 5 × ULN for cases involving liver
                  metastasis) e.Bilirubin ≤ 1.5 × ULN (≤ 5 × ULN for cases of documented or
                  suspected Gilbert's disease) f.Serum creatinine ≤ 1.5 g/dL or calculated
                  creatinine clearance (CrCl) ≥60 mL/min for patients with serum creatinine > 1.5 x
                  ULN g.Serum magnesium, calcium and potassium within normal limits 8.Life
                  expectancy ≥ 12 weeks 9.ECOG performance status (PS) < 1 10.Willing and able to
                  comply with scheduled visits, treatment plan, and laboratory tests.

                  11.Screening EKG without clinically significant abnormalities. 12.Corrected
                  (Fridericia's) QTcF must be < 480 milliseconds. 13.Allowance of prior therapy
                  regimens:

               -  No limit on prior number of regimens

               -  Must have completed prior cytotoxic chemotherapy a minimum of 4 weeks prior to
                  starting study treatment (except for bis-chlorethynitrosurea (BCNU)), which must
                  have been completed a minimum of 6 weeks prior to starting therapy.

               -  Prior localized radiation therapy must have been completed a minimum of 2 weeks
                  prior to starting therapy and the patient must have baseline imaging with a full
                  body PET-CT or CT scans of the chest, abdomen, and pelvis and within 4 weeks
                  prior to study enrollment.

               -  For CNS metastases, disease must be treated and demonstrate stability with Brain
                  MRI a minimum of 2 weeks prior to starting therapy.

                  14.Both male and female patients enrolled in this trial must agree to use highly
                  effective contraception during the course of the trial and for at least for 6
                  months after the final dose of CDX-3379 (an effective form of contraception is an
                  oral contraceptive or a double barrier method), or greater, as in accordance with
                  the label requirements for trametinib. Patients and/or partners who are
                  surgically sterile or postmenopausal are exempt from this requirement.

               -  Women of child-bearing potential, defined as all women physiologically capable of
                  becoming pregnant, unless they are using highly effective methods of
                  contraception during dosing and for 3 months after stopping study drug. Highly
                  effective contraception methods include:

               -  Total abstinence or

               -  Male or female sterilization or

               -  Combination of any two of the following (a+b or a+c or b+c):

                    1. Use of oral, injected or implanted hormonal methods of contraception;
                       hormonal contraceptives are not acceptable as a sole method of
                       contraception.

                    2. Placement of an intrauterine device (IUD) or intrauterine system (IUS)

                    3. Barrier methods of contraception: condom or occlusive cap (diaphragm or
                       cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal
                       suppository 15. 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 (e.g. age appropriate,
                       history of vasomotor symptoms) or have had surgical bilateral oophorectomy
                       (with or without 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.

        Exclusion Criteria:

          1. Received CDX-3379 or other anti-ErbB3 targeted agents previously.

          2. Received trametinib or other MEK inhibitor agents previously.

          3. Any concurrent chemotherapy, radiotherapy, immunotherapy, biologic or hormonal therapy
             for cancer treatment. Concurrent use of hormones for non-cancer related conditions
             (e.g., insulin for diabetes and hormone replacement therapy) is acceptable.

          4. Other prior malignancy active within 2 years, except for localized prostate cancer,
             cervical carcinoma in situ, non-melanomatous carcinoma of the skin, stage 1
             differentiated thyroid cancer or ductal carcinoma in situ of the breast that has/have
             undergone curative surgery or radiation.

          5. Active central nervous system (CNS) metastases are excluded. Known brain metastases
             must have been previously treated and asymptomatic for 2 weeks and not progressive in
             size or number for 4 weeks prior to enrollment, documented via scans. Continued use of
             anticonvulsants (in the absence of any suspicion of progressive brain metastases) is
             acceptable. Patients must currently be on a stable, lowest possible dose of steroids.

          6. Radiation therapy within 14 days prior to the first scheduled dose in this study,
             including, in addition (if necessary), the timeframe for resolution of any actual or
             anticipated toxicities from such radiation.

          7. Known HIV, hepatitis B or hepatitis C infection, or active infection requiring
             systemic intravenous therapy

          8. Use of any monoclonal based therapies within 4 weeks (excluding cetuximab which does
             not require a wash-out), and all other immunotherapy (tumor vaccine, cytokine, or
             growth factor given to control the cancer) within 2 weeks, prior to the first dose of
             study treatment.

          9. Chemotherapy within 4 weeks (except for bis-chlorethynitrosurea (BCNU), which must
             have been completed a minimum of 6 weeks) prior to starting therapy.

         10. Major surgery within 4 weeks prior to the first dose of study treatment. Surgery
             requiring local/epidural anesthesia must be completed at least 72 hours before study
             drug administration and patients should be recovered.

         11. Use of other investigational drugs within 2 weeks or 5 half-lives (whichever is
             longer) prior to study treatment administration

         12. A marked baseline prolongation of QT/QTc interval (e.g., repeated demonstration of a
             QTc interval >450 ms); additional risk factors for torsades de pointes (TdP) (e.g., a
             history of heart failure, family history of Long QT Syndrome, or active hypokalemia or
             uncorrectable electrolyte abnormality); significant cardiovascular disease including
             unstable angina pectoris, uncontrolled hypertension or arrhythmia, congestive heart
             failure (New York Heart Association Class III or IV) related to primary cardiac
             disease, uncontrolled ischemic or severe valvular heart disease; or any of the
             following within 6 months prior to the first dose of study treatment: myocardial
             infarction, severe/unstable angina, coronary artery bypass graft, congestive heart
             failure, cerebrovascular accident, transient ischemic attack.

         13. Requirement for chronic immunosuppressive medication including systemic
             corticosteroids above the physiologic dose (defined as 20 mg/day prednisone or the
             equivalent).

         14. Any other acute or chronic medical or psychiatric condition or laboratory abnormality
             that could increase the risk associated with trial participation or trial drug
             administration or could interfere with the interpretation of trial results and, in the
             judgment of the investigator, would make the patient inappropriate for entry into the
             trial.

         15. Known alcohol or drug abuse.

         16. Sexually active males must use a condom during intercourse while taking the drug and
             for 3 months after stopping study drug and should not father a child in this period. A
             condom is required to be used also by vasectomized men in order to prevent delivery of
             the drug via seminal fluid.

         17. Inability to swallow pills

         18. Patients unwilling or unable to comply with the protocol.
      
Maximum Eligible Age:100 Years
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Objective Response Rate
Time Frame:48 Months
Safety Issue:
Description:response rate, will becompared with the historically reported response rate for the single agent trametinib in NRAS and BRAF/NRAS WT melenoma

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:New York University School of Medicine

Last Updated