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NCT01673854

Phase II Safety Study of Vemurafenib Followed by Ipilimumab in Subjects With V600 BRAF Mutated Advanced Melanoma

Completed Phase 2 Results posted Last updated 24 July 2018
What this trial tests

Phase 2 trial testing Ipilimumab in Melanoma in 70 participants. Completed in 12 May 2015.

Timeline
13 September 2012
Primary endpoint
25 July 2014
12 May 2015

Quick facts

Lead sponsorBristol-Myers Squibb
PhasePhase 2
StatusCompleted
Study typeINTERVENTIONAL
Allocationna
Designsingle group
Maskingnone
Primary purposetreatment
Enrollment70
Start date13 September 2012
Primary completion25 July 2014
Estimated completion12 May 2015
Sites14 locations across United States

Drugs / interventions tested

Conditions studied

Sponsor

Bristol-Myers Squibb — full company profile →

Who can join

Eligibility, any sex, with 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 Who Received Ipilimumab and Who Had Grade 3-4 Drug-related Skin Adverse Events (AEs) Primary · From the first dose date of Vem1 to the last dose of ipilimumab (to a maximum of 3 years) + 90 days or to the first dose date of Vem2, whichever occurred first

AE=any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may not have a causal relationship with treatment. Drug-related=having certain, probable, possible, or unknown relationship to study drug. Grading criteria for AEs: Grade 1=Mild, Grade 2=Moderate, Grade 3=Severe, Grade 4=Life-threatening or disabling, Grade 5=Death.

GroupValue95% CI
Vemurafenib, 960 mg + Ipilimumab, 10 mg/kg32.619.5 – 48.0
Percentage of Participants Who Received Ipilimumab and Who Had Grade 3-4 Drug-related Gastrointestinal Adverse Events (AEs) Secondary · From the first dose date of Vem1 to the last dose of ipilimumab (to a maximum of 3 years) + 90 days or to the first dose date of Vem2, whichever occurred first

AE=any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may not have a causal relationship with treatment. Drug-related=having certain, probable, possible, or unknown relationship to study drug. Grading criteria for AEs: Grade 1=Mild, Grade 2=Moderate, Grade 3=Severe, Grade 4=Life-threatening or disabling, Grade 5=Death.

GroupValue95% CI
Vemurafenib, 960 mg + Ipilimumab, 10 mg/kg21.710.9 – 36.4
Percentage of Participants Who Received Ipilimumab and Who Had Grade 3-4 Drug-related Hepatobiliary Adverse Events Secondary · From the first dose date of Vem1 to the last dose of ipilimumab (to a maximum of 3 years) + 90 days or to the first dose date of Vem2, whichever occurred first

AE=any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may not have a causal relationship with treatment. Drug-related=having certain, probable, possible, or unknown relationship to study drug. Grading criteria for AEs: Grade 1=Mild, Grade 2=Moderate, Grade 3=Severe, Grade 4=Life-threatening or disabling, Grade 5=Death.

GroupValue95% CI
Vemurafenib, 960 mg + Ipilimumab, 10 mg/kg4.30.5 – 14.8
Number of Participants Who Died, Who Died Due to Related Adverse Events (AEs), and With Related AEs, Serious Adverse Events (SAEs), Related SAEs, Discontinuations Due to AEs and Related AEs, Immune-related (ir) AEs, and Serious irAEs Secondary · From the first dose date of Vem1 to the last dose of ipilimumab (to a maximum of 3 years) + 90 days or to the first dose date of Vem2, whichever occurred first

AE=any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may not have a causal relationship with treatment. SAE=a medical event that at any dose results in death, persistent or significant disability/incapacity, or drug dependency/abuse; is life-threatening, an important medical event, or a congenital anomaly/birth defect; or requires or prolongs hospitalization. Related=having certain, probable, possible, or unknown relationship to study drug.

Deaths
GroupValue95% CI
Vemurafenib, 960 mg + Ipilimumab, 10 mg/kg4
Deaths due to related AEs
GroupValue95% CI
Vemurafenib, 960 mg + Ipilimumab, 10 mg/kg0
SAEs
GroupValue95% CI
Vemurafenib, 960 mg + Ipilimumab, 10 mg/kg31
Related SAEs
GroupValue95% CI
Vemurafenib, 960 mg + Ipilimumab, 10 mg/kg18
Discontinuations due to AEs
GroupValue95% CI
Vemurafenib, 960 mg + Ipilimumab, 10 mg/kg18
Discontinuations due to related AEs
GroupValue95% CI
Vemurafenib, 960 mg + Ipilimumab, 10 mg/kg16
irAEs
GroupValue95% CI
Vemurafenib, 960 mg + Ipilimumab, 10 mg/kg43
Serious irAEs
GroupValue95% CI
Vemurafenib, 960 mg + Ipilimumab, 10 mg/kg10
Number of Participants With Adverse Events (AEs) Grade 3-4, Related AEs Grade 3-4, Related Serious Adverse Events (SAEs) Grade 3-4, Immune-related (ir) AEs Grade 3-4, and Serious irAEs Grade 3-4 Secondary · From the first dose date of Vem1 to the last dose of ipilimumab (to a maximum of 3 years) + 90 days or to the first dose date of Vem2, whichever occurred first

AE=any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may not have a causal relationship with treatment. SAE=a medical event that at any dose results in death, persistent or significant disability/incapacity, or drug dependency/abuse; is life-threatening, an important medical event, or a congenital anomaly/birth defect; or requires or prolongs hospitalization. Related=having certain, probable, possible, or unknown relationship to study drug. Grade 1=Mild, Grade 2=Moderate, Grade 3=Severe, Grade 4=Life-threatening or disabling, Grade 5=Death.

AEs Grade 3-4
GroupValue95% CI
Vemurafenib, 960 mg + Ipilimumab, 10 mg/kg39
Related AEs Grade 3-4
GroupValue95% CI
Vemurafenib, 960 mg + Ipilimumab, 10 mg/kg30
Related SAEs Grade 3-4
GroupValue95% CI
Vemurafenib, 960 mg + Ipilimumab, 10 mg/kg17
irAEs Grade 3-4
GroupValue95% CI
Vemurafenib, 960 mg + Ipilimumab, 10 mg/kg25
Serious irAEs Grade 3-4
GroupValue95% CI
Vemurafenib, 960 mg + Ipilimumab, 10 mg/kg9

Adverse events — posted to ClinicalTrials.gov

Time frame: AEs with onset date on or after Day 1 of study therapy and within the last dose of Vem1 + 14 days, last dose of Ipi Phase + 90 days, last dose of Vem2 + 14 days. Up to July 2014 (approximately 21 months). Reporting threshold: 5%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Vemurafenib, 960 mg + Ipilimumab,10 mg/kg ab
Serious: 34/46 (74%)
Deaths:

Serious adverse events (53 terms)

ReactionSystemVemurafenib, 960 mg + Ipil…
Malignant neoplasm progressionNeoplasms benign, malignant and unspecified (incl cysts and polyps)
ColitisGastrointestinal disorders
AstheniaGeneral disorders
Pain in extremityMusculoskeletal and connective tissue disorders
Squamous cell carcinomaNeoplasms benign, malignant and unspecified (incl cysts and polyps)
Back painMusculoskeletal and connective tissue disorders
DehydrationMetabolism and nutrition disorders
HeadacheNervous system disorders
VomitingGastrointestinal disorders
DiarrhoeaGastrointestinal disorders
HypotensionVascular disorders
PainGeneral disorders
Abdominal painGastrointestinal disorders
DysphagiaGastrointestinal disorders
PyrexiaGeneral disorders
Haemorrhage IntracranialNervous system disorders
HepatitisHepatobiliary disorders
HypoxiaRespiratory, thoracic and mediastinal disorders
Renal failureRenal and urinary disorders
Tumour painNeoplasms benign, malignant and unspecified (incl cysts and polyps)
AbasiaGeneral disorders
Adenocarcinoma of colonNeoplasms benign, malignant and unspecified (incl cysts and polyps)
Iliac vein occlusionVascular disorders
PancreatitisGastrointestinal disorders
Pericardial effusionCardiac disorders
Other adverse events (77 terms — click to expand)

ReactionSystemVemurafenib, 960 mg + Ipil…
RashSkin and subcutaneous tissue disorders
ArthralgiaMusculoskeletal and connective tissue disorders
FatigueGeneral disorders
DiarrhoeaGastrointestinal disorders
NauseaGastrointestinal disorders
Decreased appetiteMetabolism and nutrition disorders
PruritusSkin and subcutaneous tissue disorders
VomitingGastrointestinal disorders
HeadacheNervous system disorders
InsomniaPsychiatric disorders
PyrexiaGeneral disorders
Abdominal painGastrointestinal disorders
Pain in extremityMusculoskeletal and connective tissue disorders
Blood alkaline phosphatase increasedInvestigations
DizzinessNervous system disorders
Oedema peripheralGeneral disorders
Aspartate aminotransferase increasedInvestigations
Back painMusculoskeletal and connective tissue disorders
AnaemiaBlood and lymphatic system disorders
ChillsGeneral disorders
Alanine aminotransferase increasedInvestigations
Dry skinSkin and subcutaneous tissue disorders
DysgeusiaNervous system disorders
ConstipationGastrointestinal disorders
MyalgiaMusculoskeletal and connective tissue disorders
DyspnoeaRespiratory, thoracic and mediastinal disorders
CoughRespiratory, thoracic and mediastinal disorders
Vision blurredEye disorders
HypokalaemiaMetabolism and nutrition disorders
Blood creatinine increasedInvestigations
Muscular weaknessMusculoskeletal and connective tissue disorders
HyperglycaemiaMetabolism and nutrition disorders
Photosensitivity reactionSkin and subcutaneous tissue disorders
HypophysitisEndocrine disorders
AlopeciaSkin and subcutaneous tissue disorders
HyponatraemiaMetabolism and nutrition disorders
Palmar-plantar erythrodysaesthesia syndromeSkin and subcutaneous tissue disorders
Rash maculo-papularSkin and subcutaneous tissue disorders
HypomagnesaemiaMetabolism and nutrition disorders
ColitisGastrointestinal disorders

Most-reported serious reactions: Malignant neoplasm progression, Colitis, Asthenia, Pain in extremity, Squamous cell carcinoma, Back pain, Dehydration, Headache.

Data from ClinicalTrials.gov NCT01673854 adverse events section.

Sponsor's own description

The purpose of this study is to assess the safety profile of vemurafenib, 960 mg, administered for 6 weeks, followed by ipilimumab monotherapy in patients with BRAF V600 mutated advanced/metastatic melanoma.

Publications & conference data

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

  1. At the bedside: CTLA-4- and PD-1-blocking antibodies in cancer immunotherapy.
    Callahan MK, Wolchok JD. · · 2013 · cited 246× · PMID 23667165 · DOI 10.1189/jlb.1212631
  2. Combining Immune Checkpoint Inhibitors With Conventional Cancer Therapy.
    Yan Y, Kumar AB, Finnes H, Markovic SN, et al · · 2018 · cited 163× · PMID 30100909 · DOI 10.3389/fimmu.2018.01739
  3. Combining targeted therapy with immunotherapy in BRAF-mutant melanoma: promise and challenges.
    Hu-Lieskovan S, Robert L, Homet Moreno B, Ribas A. · · 2014 · cited 150× · PMID 24958825 · DOI 10.1200/jco.2013.52.1377
  4. Current Advances in the Treatment of BRAF-Mutant Melanoma.
    Patel H, Yacoub N, Mishra R, White A, et al · · 2020 · cited 133× · PMID 32092958 · DOI 10.3390/cancers12020482
  5. Cytotoxic T lymphocyte antigen-4 and immune checkpoint blockade.
    Buchbinder E, Hodi FS. · · 2015 · cited 130× · PMID 26325034 · DOI 10.1172/jci80012
  6. Combined targeted therapy and immunotherapy in melanoma: a review of the impact on the tumor microenvironment and outcomes of early clinical trials.
    Pelster MS, Amaria RN. · · 2019 · cited 102× · PMID 30815041 · DOI 10.1177/1758835919830826
  7. Overcoming resistance to BRAF inhibition in BRAF-mutated metastatic melanoma.
    Spagnolo F, Ghiorzo P, Queirolo P. · · 2014 · cited 92× · PMID 25344914 · DOI 10.18632/oncotarget.2602
  8. Combination of Immunotherapy With Targeted Therapy: Theory and Practice in Metastatic Melanoma.
    Yu C, Liu X, Yang J, Zhang M, et al · · 2019 · cited 86× · PMID 31134073 · DOI 10.3389/fimmu.2019.00990

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