NCT01253564

A Study of RO5185426 in Previously Treated Melanoma Patients With Brain Metastases

Completed Phase 2 Results posted Last updated 31 July 2017

What this trial tests

Phase 2 trial testing RO5185426 in Malignant Melanoma in 24 participants. Completed in 14 March 2012.

Timeline

22 November 2010

Primary endpoint
14 March 2012

14 March 2012

Quick facts

Lead sponsor	Hoffmann-La Roche
Phase	Phase 2
Status	Completed
Study type	INTERVENTIONAL
Allocation	na
Design	single group
Masking	none
Primary purpose	treatment
Enrollment	24
Start date	22 November 2010
Primary completion	14 March 2012
Estimated completion	14 March 2012
Sites	2 locations across Switzerland

Drugs / interventions tested

• RO5185426 — full drug profile →

Conditions studied

• Malignant Melanoma — all drugs for Malignant Melanoma →

Sponsor

Hoffmann-La Roche — full company profile →

Who can join

18 and older, any sex, with Malignant Melanoma. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Percentage of Participants With Adverse Events (AEs) Primary · From baseline up to last dose (0.1 to 11.3 months) plus 28 days

AE:any unfavorable and unintended sign, symptom, or disease associated with use of study drug, regardless of relation to study drug. Pre-existing conditions that worsened and laboratory or clinical tests that resulted in change in treatment or discontinuation from study drug were reported as AEs. Serious AE: resulted in death, life-threatening, required in-patient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, was congenital anomaly/birth defect or was medically significant. Grade-1:discomfort but no disruption of norma

Any AEs

Group	Value	95% CI
Vemurafenib	96

Drug-related AEs

Group	Value	95% CI
Vemurafenib	83

AEs of Grade 1 and 2

Group	Value	95% CI
Vemurafenib	92

AEs of Grade 3

Group	Value	95% CI
Vemurafenib	17

AEs of Grade 5

Group	Value	95% CI
Vemurafenib	4

SAEs

Group	Value	95% CI
Vemurafenib	58

Drug-related SAEs

Group	Value	95% CI
Vemurafenib	17

AEs that led to Study Drug Discontinuation

Group	Value	95% CI
Vemurafenib	4

Percentage of Participants With a Best Overall Response of Complete Response (CR) or Partial Response (PR) by Disease Site Secondary · Baseline, Week 4, Week 8 and thereafter every 8th week until progressive disease, unacceptable toxicity, consent withdrawal, death or other reasons deemed by the investigator (up to 16 months)

Objective response was assessed by the investigator according to Response Evaluation Criteria in Solid Tumours (RECIST) (Version 1.1). CR was defined as disappearance of all target and non-target lesions and no new lesions. PR was defined as at least a 30% decrease in the sum of diameters of target lesions (taking as reference the baseline sum diameters), no progression in non-target lesions, and no new lesions. Best overall response was calculated separately for brain, other sites (extracranial) and whole body. Percentage of participants with 95 percent (%) Clopper-Pearson confidence interval

Brain (n=19)

Group	Value	95% CI
Vemurafenib	15.8	3.4 – 39.6

Extracranial (n=21)

Group	Value	95% CI
Vemurafenib	61.9	38.4 – 81.9

Whole body (n=24)

Group	Value	95% CI
Vemurafenib	41.7	22.1 – 63.4

Duration of Response by Disease Site Secondary · Baseline, Week 4, Week 8 and thereafter every 8th week until progressive disease or death (up to 16 months)

Duration of response was defined as the time interval between the date of the earliest qualifying response and the date of progressive disease (PD) or death, only for those participants whose best overall response was CR or PR. CR and PR were assessed by investigator according to RECIST version 1.1. CR was defined as disappearance of all target and non-target lesions and no new lesions. PR was defined as at least a 30% decrease in the sum of diameters of target lesions (taking as reference the baseline sum diameters), no progression in non-target lesions, and no new lesions. PD was defined as

Brain (n=3)

Group	Value	95% CI
Vemurafenib	4.4	2.1 – 4.6

Extracranial (n=13)

Group	Value	95% CI
Vemurafenib	3.8	2.7 – 5.3

Whole body (n=10)

Group	Value	95% CI
Vemurafenib	3.7	2.7 – 4.8

Time to Response by Disease Site Secondary · Baseline, Week 4, Week 8 and thereafter every 8th week until progressive disease, unacceptable toxicity, consent withdrawal, death or other reasons deemed by the investigator (up to 16 months)

Time to response was defined as the interval between the date of first treatment and the date of first documentation of CR or PR (whichever occurred first). CR and PR were assessed by investigator according to RECIST version 1.1. CR was defined as disappearance of all target and non-target lesions and no new lesions. PR was defined as at least a 30% decrease in the sum of diameters of target lesions (taking as reference the baseline sum diameters), no progression in non-target lesions, and no new lesions. Time of response was calculated by Kaplan-Meier estimates separately for brain, other sit

Brain (n=19)

Group	Value	95% CI
Vemurafenib	NA	NA – NA

Extracranial (n=20)

Group	Value	95% CI
Vemurafenib	1.4	0.9 – NA

Whole body (n=23)

Group	Value	95% CI
Vemurafenib	5.5	1.8 – NA

Duration of Stable Disease (SD) by Disease Site Secondary · Baseline, Week 4, Week 8 and thereafter every 8th week until progressive disease, unacceptable toxicity, consent withdrawal, death or other reasons deemed by the investigator (up to 16 months)

Duration of SD was defined as the time between the first documented date of SD and date of PD or death from any cause. SD was defined (according to RECIST version 1.1) as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. PR was defined as at least a 30% decrease in the sum of diameters of target lesions (taking as reference the baseline sum diameters), no progression in non-target lesions, and no new lesions. PD was defined as at least 20% increase in the sum of diameters of target lesions co

Brain (n=13)

Group	Value	95% CI
Vemurafenib	5.5	4.1 – 5.6

Extracranial (n=6)

Group	Value	95% CI
Vemurafenib	3.9	2.3 – 12.1

Whole body (n=9)

Group	Value	95% CI
Vemurafenib	3.9	3.7 – 5.6

Time to New Lesion by Disease Site Secondary · Baseline, Week 4, Week 8 and thereafter every eighth week until progressive disease, unacceptable toxicity, consent withdrawal, death or other reasons deemed by the investigator (up to 16 months)

Time to new lesions was defined as the interval between the date of first treatment and the date of first documentation of new lesions. Time to new lesion was calculated by Kaplan-Meier estimates separately for brain, other sites (extracranial) and whole body.

Brain (n=23)

Group	Value	95% CI
Vemurafenib	5.6	3.9 – NA

Extracranial (n=23)

Group	Value	95% CI
Vemurafenib	NA	NA – NA

Whole body (n=23)

Group	Value	95% CI
Vemurafenib	5.6	3.9 – NA

Percentage of Participants With Disease Progression or Death by Disease Site Secondary · Baseline, Week 4, Week 8 and thereafter every 8th week until progressive disease, unacceptable toxicity, consent withdrawal, death or other reasons deemed by the investigator (up to 16 months)

Disease progression (according to RECIST version 1.1) was defined as at least 20% increase in the sum of diameters of target lesions compared to smallest sum of diameters on-study or absolute increase and at least 5 mm, progression of existing non-target lesions, or presence of new lesions. Percentage of participants with disease progression by brain, other sites (extracranial) and whole body are reported.

Brain

Group	Value	95% CI
Vemurafenib	100

Extracranial

Group	Value	95% CI
Vemurafenib	83.3

Whole body

Group	Value	95% CI
Vemurafenib	100

Progression Free Survival (PFS) Secondary · Baseline, Week 4, Week 8 and thereafter every eighth week until progressive disease, unacceptable toxicity, consent withdrawal, death or other reasons deemed by the investigator (up to 16 months)

PFS was defined as the time interval between the date of the first treatment and the date of progression or death from any cause, whichever occurred first. Disease progression (according to RECIST version 1.1) was defined as at least 20% increase in the sum of diameters of target lesions compared to smallest sum of diameters on-study or absolute increase and at least 5 mm, progression of existing non-target lesions, or presence of new lesions. PFS was calculated by Kaplan-Meier estimates separately for brain, other sites (extracranial) and whole body.

Brain

Group	Value	95% CI
Vemurafenib	4.3	3.1 – 5.5

Extracranial

Group	Value	95% CI
Vemurafenib	4.6	3.1 – 5.6

Whole body

Group	Value	95% CI
Vemurafenib	3.9	3.0 – 5.5

Percentage of Participants Who Died Secondary · Baseline up to end of the study and every 3 months during follow-up (up to 16 months)

Percentage of participants who died due to any reason are reported.

Group	Value	95% CI
Vemurafenib	79.2

Overall Survival (OS) Secondary · From start of treatment up to end of the study and every 3 months during follow up (up to 16 months)

OS was defined as the time from the date of first treatment to the date of death, regardless of the cause of death. Participants who discontinued the study treatment for any reason other than withdrawal of consent were continued to be followed for survival. The end of study occurred when all participants had been followed for a period of 6 months, had died, withdrawn consent or were lost to follow-up, whichever occurred first. OS was calculated by Kaplan-Meier estimates.

Group	Value	95% CI
Vemurafenib	5.3	3.9 – 6.6

Percentage of Participants With Improvement in Total Daily Dose of Corticosteroids Secondary · Baseline, every week during the first 8 weeks and every second week thereafter up to last dose (0.1 to 11.3 months) plus 28 days

An improvement in corticosteroid dose was defined as a dose reduction of at least 33% of baseline dose for at least 28 days or stopping use completely. Percentage of participants and 95% Clopper-Pearson CI are reported.

Group	Value	95% CI
Vemurafenib	66.7	44.7 – 84.4

Percentage of Participants With Improvement in Total Daily Dose of Narcotic Pain Analgesic Secondary · Baseline, every week during the first 8 weeks and every second week thereafter up to last dose (0.1 to 11.3 months) plus 28 days

An improvement in narcotic pain analgesics was defined as a dose reduction of at least 33% of baseline dose for at least 28 days or stopping use completely.

Group	Value	95% CI
Vemurafenib	8.3

Adverse events — posted to ClinicalTrials.gov

Time frame: From baseline up to last dose (0.1 to 11.3 months) plus 28 days. Reporting threshold: 5%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Vemurafenib

Serious: 14/24 (58%)

Deaths: —

Serious adverse events (11 terms)

Reaction	System	Vemurafenib
Epilepsy	Nervous system disorders	—
Squamous cell carcinoma of skin	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	—
Cerebral disorder	Nervous system disorders	—
Constipation	Gastrointestinal disorders	—
Ileus	Gastrointestinal disorders	—
Chest discomfort	General disorders	—
Erysipelas	Infections and infestations	—
Humerus fracture	Injury, poisoning and procedural complications	—
C-reactive protein increased	Investigations	—
Confusional state	Psychiatric disorders	—
Dyspnoea	Respiratory, thoracic and mediastinal disorders	—

Other adverse events (37 terms — click to expand)

Reaction	System	Vemurafenib
Arthralgia	Musculoskeletal and connective tissue disorders	—
Alopecia	Skin and subcutaneous tissue disorders	—
Solar dermatitis	Skin and subcutaneous tissue disorders	—
Rash maculo-papular	Skin and subcutaneous tissue disorders	—
Dizziness	Nervous system disorders	—
Paraesthesia	Nervous system disorders	—
Muscular weakness	Musculoskeletal and connective tissue disorders	—
Vomiting	Gastrointestinal disorders	—
Diarrhoea	Gastrointestinal disorders	—
Hyperkeratosis	Skin and subcutaneous tissue disorders	—
Oral candidiasis	Infections and infestations	—
Fatigue	General disorders	—
Oedema peripheral	General disorders	—
Dysgeusia	Nervous system disorders	—
Headache	Nervous system disorders	—
Oral herpes	Infections and infestations	—
Papilloma	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	—
Skin papilloma	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	—
Cough	Respiratory, thoracic and mediastinal disorders	—
Sleep disorder	Psychiatric disorders	—
Haematoma	Vascular disorders	—
Keratosis pilaris	Skin and subcutaneous tissue disorders	—
Photosensitivity reaction	Skin and subcutaneous tissue disorders	—
Pruritus	Skin and subcutaneous tissue disorders	—
Epilepsy	Nervous system disorders	—
Ageusia	Nervous system disorders	—
Back pain	Musculoskeletal and connective tissue disorders	—
Muscle spasms	Musculoskeletal and connective tissue disorders	—
Abdominal pain	Gastrointestinal disorders	—
Constipation	Gastrointestinal disorders	—
Nausea	Gastrointestinal disorders	—
Folliculitis	Infections and infestations	—
Influenza	Infections and infestations	—
Oropharyngeal pain	Respiratory, thoracic and mediastinal disorders	—
Anaemia	Blood and lymphatic system disorders	—
Hearing impaired	Ear and labyrinth disorders	—
Alanine aminotransferase increased	Investigations	—

Most-reported serious reactions: Epilepsy, Squamous cell carcinoma of skin, Cerebral disorder, Constipation, Ileus, Chest discomfort, Erysipelas, Humerus fracture.

Data from ClinicalTrials.gov NCT01253564 adverse events section.

Sponsor's own description

This open-label study will assess the safety and efficacy of RO5185426 in previously treated metastatic melanoma patients with brain metastases. Patients will receive RO5185426 at a dose of 960 mg twice daily orally until disease progression or unacceptable toxicity occurs.

Publications & conference data

3 peer-reviewed publications reference this trial (live from Europe PMC):

1. Targeting the ERK Signaling Pathway in Melanoma.
   Savoia P, Fava P, Casoni F, Cremona O. · · 2019 · cited 137× · PMID 30934534 · DOI 10.3390/ijms20061483
2. RASopathic skin eruptions during vemurafenib therapy.
   Rinderknecht JD, Goldinger SM, Rozati S, Kamarashev J, et al · · 2013 · cited 48× · PMID 23516541 · DOI 10.1371/journal.pone.0058721
3. Melanoma brain metastases: review of histopathological features and immune-molecular aspects.
   Salvati L, Mandalà M, Massi D. · · 2020 · cited 6× · PMID 32821376 · DOI 10.2217/mmt-2019-0021