Selumetinib (AZD6244: ARRY-142886) (Hyd-Sulfate) in Metastatic Uveal Melanoma (SUMIT) (SUMIT)

• ClinicalTrials.gov Identifier: NCT01974752
• Recruitment Status: Completed
• First Posted: November 3, 2013
• Results First Posted: September 28, 2016
• Last Update Posted: January 5, 2017
• Sponsor: AstraZeneca
• Information provided by (Responsible Party): AstraZeneca

Tracking Information

• First Submitted Date: October 10, 2013
• First Posted Date: November 3, 2013
• Results First Submitted Date: May 9, 2016
• Results First Posted Date: September 28, 2016
• Last Update Posted Date: January 5, 2017
• Study Start Date: April 2014
• Actual Primary Completion Date: May 2015 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: August 5, 2016)

Assessment of the Efficacy of Selumetinib in Combination With Dacarbazine Compared With Placebo in Combination With Dacarbazine Measured as Progression Free Survival (PFS) Using BICR According to RECIST 1.1. [ Time Frame: From Randomization, then every 6 weeks up until progression or death (whichever is sooner) assessed up to 15th May 2015 ]

Progression free survival (PFS) using blinded independent central review (BICR) according to the Response Evaluation Criteria in Solid Tumours version 1.1 (RECIST 1.1). Progression is defined as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.

Original Primary Outcome Measures (submitted: October 28, 2013)

Progression Free Survival (PFS) by Blind Independent Central Review (BICR) according to RECIST 1.1 [ Time Frame: Radiological scans performed from baseline then every 6 weeks until disease progression is confirmed by BICR in accordance with RECIST 1.1, assessed up to 18 months ]

To assess the efficacy of selumetinib in combination with dacarbazine with placebo in combination with dacarbazine in terms of PFS

Current Secondary Outcome Measures (submitted: August 5, 2016)

• Assessment of the Efficacy of Selumetinib in Combination With Dacarbazine Compared With Placebo in Combination With Dacarbazine in Terms of Objective Response Rate (ORR) by BICR [ Time Frame: From Randomization, then every 6 weeks up until progression or death (whichever is sooner) assessed up to 15th May 2015 ]
  ORR at Week 6 using BICR according to RECIST 1.1
• Assessment of the Efficacy of Selumetinib in Combination With Dacarbazine Compared With Placebo in Combination With Dacarbazine in Terms of Change in Tumour Size at Week 6 by BICR [ Time Frame: From Randomization, then every 6 weeks up until progression or death (whichever is sooner) assessed up to 15th May 2015 ]
  Percent change in tumour size at Week 6 using BICR according to RECIST 1.1
• Assessment of the Overall Survival (OS) in Patients Taking Selumetinib in Combination With Dacarbazine Compared With Those Taking Placebo in Combination With Dacarbazine [ Time Frame: From Randomization, up until death assessed up to 15th May 2015 ]
  Overall Survival

Original Secondary Outcome Measures (submitted: October 28, 2013)

• Objective Response Rate (ORR) by central review of RECIST data [ Time Frame: From baseline and at every 6 weeks, up to 18 months ]
  To assess the efficacy of selumetinib in combination with dacarbazine with placebo in combination with dacarbazine by assessment of Objective Response Rate
• Duration of Response by central review of RECIST data. [ Time Frame: From baseline and at every 6 weeks, up to 18 months ]
  To assess the efficacy of selumetinib in combination with dacarbazine with placebo in combination with dacarbazine by assessment of Duration of response
• Change in tumour size by central review of RECIST data. [ Time Frame: From baseline and at every 6 weeks, up to 18 months ]
  To assess the efficacy of selumetinib in combination with dacarbazine with placebo in combination with dacarbazine by assessment of change in tumour size
• Efficacy in patients by assessment of overall survival [ Time Frame: Post -progression patients assessed for survival every 8 weeks, up to 30 months ]
  To assess Overall survival in patients taking selumetinib in combination with dacarbazine compared with those taking placebo in combination with dacarbazine
• Assessment of the safety and tolerability of selumetinib by collection of adverse event reports [ Time Frame: From baseline and at each study visit up to 30 months ]
  Assessment of adverse events (AEs) graded by Common Terminology Criteria for Adverse Events (CTCAE) v4.0
• Determine safety and tolerability of selumetinib by assessment of 12 lead electrocardiograms [ Time Frame: From baseline, up to 30 months ]
  Assessment of standard 12 lead electrocardiograms (ECGs)
• Determine safety and tolerability of selumetinib by assessment of vital signs [ Time Frame: From baseline and at each study visit up to 30 months ]
  Assessment of standard vital signs (including blood pressure, pulse)
• Determine safety and tolerability of selumetinib by assessment of clinical chemistry results [ Time Frame: From baseline and at each study visit up to 30 months ]
  Assessment of laboratory parameters (clinical chemistry)
• Determine safety and tolerability of selumetinib by assessment of haematology results [ Time Frame: From baseline and at each study visit up to 30 months ]
  Assessment of laboratory parameters (haematology)
• Determine safety and tolerability of selumetinib by assessment of urinalysis results [ Time Frame: From baseline and at each study visit up to 30 months ]
  Assessment of laboratory parameters (urinalysis)
• Determine safety and tolerability of selumetinib by assessment of Echocardiogram/Multi gated Acquisition Scan (MUGA) [ Time Frame: From baseline and every 12 weeks up to 30 months. ]
  Assessment of MUGA
• Determine safety and tolerability of selumetinib by Ophthalmologic assessment [ Time Frame: From baseline, up to 30 months ]
  Ophthalmological assessment

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Selumetinib (AZD6244: ARRY-142886) (Hyd-Sulfate) in Metastatic Uveal Melanoma (SUMIT)
• Official Title: A Randomised, Double-Blind Study to Assess the Efficacy of Selumetinib (AZD6244: ARRY-142886) (Hyd-Sulfate) in Combination With Dacarbazine Compared With Placebo in Combination With Dacarbazine as First Systemic Therapy in Patients With Metastatic Uveal Melanoma (SUMIT)
• Brief Summary: Selumetinib therapy in patients with metastatic uveal melanoma.
• Detailed Description: A randomised double-blind study to assess the efficacy of selumetinib (AZD6244, Hyd-Sulfate) in combination with Dacarbazine compared with placebo in combination with Dacarbazine as first systemic therapy in patients with metastatic uveal melanoma (SUMIT)
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment

Condition

• Metastatic
• Uveal Melanoma

Intervention

• Drug: 75mg selumetinib
  selumetinib tablets p.o. twice daily taken in combination with dacarbazine 1000mg/m2 iv on day 1 of every 21-day cycle.
• Drug: placebo
  placebo tablets p.o. twice daily taken in combination with dacarbazine 1000mg/m2 iv on day 1 of every 21-day cycle.
• Drug: Dacarbazine
  dacarbazine 1000mg/m2 iv on day 1 of every 21-day cycle taken in combination with either selumetinib or placebo tablets p.o. twice daily.

Study Arms

• Experimental: selumetinib 75mg twice daily
  selumetinib 75mg twice daily in combination with dacarbazine.
  Interventions:

  • Drug: 75mg selumetinib
  • Drug: Dacarbazine
• Placebo Comparator: placebo twice daily
  placebo twice daily in combination with dacarbazine.
  Interventions:

  • Drug: placebo
  • Drug: Dacarbazine

Publications *

• Carvajal RD, Piperno-Neumann S, Kapiteijn E, Chapman PB, Frank S, Joshua AM, Piulats JM, Wolter P, Cocquyt V, Chmielowski B, Evans TRJ, Gastaud L, Linette G, Berking C, Schachter J, Rodrigues MJ, Shoushtari AN, Clemett D, Ghiorghiu D, Mariani G, Spratt S, Lovick S, Barker P, Kilgour E, Lai Z, Schwartz GK, Nathan P. Selumetinib in Combination With Dacarbazine in Patients With Metastatic Uveal Melanoma: A Phase III, Multicenter, Randomized Trial (SUMIT). J Clin Oncol. 2018 Apr 20;36(12):1232-1239. doi: 10.1200/JCO.2017.74.1090. Epub 2018 Mar 12. Erratum In: J Clin Oncol. 2018 Dec 10;36(35):3528.
• Carvajal RD, Schwartz GK, Mann H, Smith I, Nathan PD. Study design and rationale for a randomised, placebo-controlled, double-blind study to assess the efficacy of selumetinib (AZD6244; ARRY-142886) in combination with dacarbazine in patients with metastatic uveal melanoma (SUMIT). BMC Cancer. 2015 Jun 10;15:467. doi: 10.1186/s12885-015-1470-z.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: July 6, 2015): 152
• Original Estimated Enrollment (submitted: October 28, 2013): 128
• Actual Study Completion Date: October 2016
• Actual Primary Completion Date: May 2015 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria: Clinical diagnosis of metastatic uveal melanoma; Written consent from female or male patients aged 18 years and over. Histological or cytological confirmation of melanoma who are suitable for treatment with dacarbazine chemotherapy.

• At least one lesion that can be accurately measured at baseline as>/=10mm in the longest diameter. (except lymph nodes which must have short axis ≥15 mm) with CT or MRI and which is suitable for accurate repeated measurements
• ECOG performance status 0-1
• life expectancy >12 weeks
• Normal organ and marrow function
• Evidence of post-menopausal status, or negative urinary or serum pregnancy test for female pre-menopausal patients
• Patients should be able to swallow selumetinib/placebo capsules

Exclusion Criteria:-Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site)

• Previous randomisation in the present study
• Patients cannot have previously been treated with a systemic anti-cancer therapy. Patients can have prior intra-hepatic or non-systemic therapy. -Having received any of the following within the specified timeframe:

Any prior systemic anti-cancer therapy for the treatment of this current diagnosis, An investigational drug within 30 days of starting treatment or within five half-lives of the compound (whichever is the most appropriate is at the discretion of the Investigator), or have not recovered from side effects of an investigational drug Any non-systemic anti-cancer therapy which has not been cleared from the body by the time of starting study treatment Radiation therapy within 4 weeks prior to starting study treatment, or limited field of radiation for palliation within 7 days of the first dose of study treatment Major surgery within 4 weeks prior to entry into the study (excluding the placement of vascular access) which would prevent administration of study treatment, Any prior investigational therapy comprising inhibitors of RAS, RAF or MEK at any time, Previous treatment with dacarbazine. Any unresolved toxicity >CTCAE grade 2 from previous anti-cancer therapy, excluding alopecia -History of allergic reactions attributed to compounds of similar chemical or biologic composition to selumetinib or dacarbazine

--Symptomatic brain metastases or spinal cord compression (patients must be treated and stable off steroids and anti-convulsants for at least 1 month prior to entry into the study)

Cardiac conditions as follows:

• Uncontrolled hypertension (BP ≥150/95 mmHg despite medical therapy)
• Acute coronary syndrome within 6 months prior to starting treatment
• Uncontrolled Angina - Canadian Cardiovascular Society grade II-IV despite medical therapy - Symptomatic heart failure (New York Heart Association [NYHA] Class II-IV,- Prior or current cardiomyopathy
• Baseline LVEF <55% measured by echocardiography or MUGA. Appropriate correction to be used if a MUGA is performed
• Severe valvular heart disease
• Atrial fibrillation with a ventricular rate >100 bpm on ECG at rest
• QTcF >450 ms or other factors that increase the risk of QTc prolongation
• Any evidence of severe or uncontrolled systemic disease, active infection, active bleeding diatheses or renal transplant, including any patient known to have hepatitis B, hepatitis C or human immunodeficiency virus (HIV)
• Refractory nausea and vomiting, chronic gastrointestinal diseases (eg inflammatory bowel disease), or significant bowel resection that would preclude adequate absorption
• History of another primary malignancy within 5 years prior to starting study treatment, except for adequately treated basal or squamous cell carcinoma of the skin or cancer of the cervix in situ and the disease under study
• Ophthalmologic conditions:
• Current or past history of central serous retinopathy
• Current or past history of retinal vein occlusion
• IOP >21 mmHg or uncontrolled glaucoma (irrespective of IOP)
• Female patients who are breast-feeding a child and male or female patients of reproductive potential who are not employing an effective method of birth control
• Clinical judgement by the Investigator that the patient should not participate in the study.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 130 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Belgium, Canada, Czech Republic, Finland, France, Germany, Israel, Netherlands, Spain, United Kingdom, United States

Administrative Information

• NCT Number: NCT01974752
• Other Study ID Numbers: D1344C00001
• Has Data Monitoring Committee: No
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: AstraZeneca
• Original Responsible Party: Same as current
• Current Study Sponsor: AstraZeneca
• Original Study Sponsor: Same as current
• Collaborators: Not Provided
• Investigators: Not Provided
• PRS Account: AstraZeneca
• Verification Date: January 2017