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NCT02855944

ARIEL4: A Study of Rucaparib Versus Chemotherapy BRCA Mutant Ovarian, Fallopian Tube, or Primary Peritoneal Cancer Patients

Completed Phase 3 Results posted Last updated 9 June 2023
What this trial tests

Phase 3 trial testing Chemotherapy in Ovarian Cancer in 349 participants. Completed in 16 September 2022.

Timeline
1 March 2017
Primary endpoint
3 December 2020
16 September 2022

Quick facts

Lead sponsorpharmaand GmbH
PhasePhase 3
StatusCompleted
Study typeINTERVENTIONAL
Allocationrandomized
Designparallel
Maskingnone
Primary purposetreatment
Enrollment349
Start date1 March 2017
Primary completion3 December 2020
Estimated completion16 September 2022
Sites77 locations across Italy, Russia, Ukraine, United Kingdom, Israel, Hungary, Poland, Canada

Drugs / interventions tested

Conditions studied

Sponsor

pharmaand GmbH — full company profile →

Who can join

18 and older, female only, with Ovarian Cancer or Epithelial Ovarian Cancer. 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.

Investigator Assessed Progression-Free Survival (invPFS) by RECIST Version 1.1 for Rucaparib Versus Chemotherapy (Efficacy Population) Primary · Assessments every 8 weeks from Cycle 1 Day 1 (C1D1) until disease progression, death, or initiation of subsequent treatment. After 18 months on study, assessments every 16 weeks. Total follow-up was up to approximately 3.5 years.

The primary efficacy endpoint is invPFS for the Treatment Part of the study. The time to invPFS is calculated in months as the time from randomization to disease progression +1 day, as determined by RECIST v1.1 (Response Evaluation Criteria in Solid Tumors) criteria or death due to any cause, whichever occurs first. Progression is defined using RECIST v1.1, as at least 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.

GroupValue95% CI
Rucaparib7.47.3 – 9.1
Chemotherapy5.75.5 – 7.3
Investigator Assessed Progression-Free Survival (invPFS) by RECIST Version 1.1 for Rucaparib Versus Chemotherapy (ITT Population) Primary · Assessments every 8 weeks from C1D1 until disease progression, death, or initiation of subsequent treatment. After 18 months on study, assessments every 16 weeks. Total follow-up was up to approximately 3.5 years.

The primary efficacy endpoint is invPFS for the Treatment Part of the study. The time to invPFS is calculated in months as the time from randomization to disease progression +1 day, as determined by RECIST v1.1 (Response Evaluation Criteria in Solid Tumors) criteria or death due to any cause, whichever occurs first. Progression is defined using RECIST v1.1, as at least 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.

GroupValue95% CI
Rucaparib7.46.7 – 7.9
Chemotherapy5.75.5 – 6.7
Investigator Assessed Overall Response Rate (ORR) by RECIST v1.1 (Efficacy Population) Secondary · Assessments every 8 weeks from C1D1 until disease progression, death, or initiation of subsequent treatment. After 18 months on study, assessments every 16 weeks. Total follow-up was up to approximately 3.5 years.

A secondary endpoint is the ORR for the Treatment Part of the study. ORR is defined as the percentage of patients with a confirmed CR (complete response) or PR (partial response) by RECIST v1.1. The confirmed response is defined as a CR or PR on subsequent tumor assessment at least 28 days after first response documentation. CR is disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. PR is at least a 30% decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum of

GroupValue95% CI
Rucaparib40.333.6 – 47.2
Chemotherapy32.323.1 – 42.6
Investigator Assessed Overall Response Rate (ORR) by RECIST v1.1 (ITT Population) Secondary · Assessments every 8 weeks from C1D1 until disease progression, death, or initiation of subsequent treatment. After 18 months on study, assessments every 16 weeks. Total follow-up was up to approximately 3.5 years.

A secondary endpoint is the ORR for the Treatment Part of the study. ORR is defined as the percentage of patients with a confirmed CR (complete response) or PR (partial response) by RECIST v1.1. The confirmed response is defined as a CR or PR on subsequent tumor assessment at least 28 days after first response documentation. CR is disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. PR is at least a 30% decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum of

GroupValue95% CI
Rucaparib37.931.6 – 44.7
Chemotherapy30.221.7 – 39.9
Investigator Assessed Duration of Response (DOR) by RECIST v1.1 (Efficacy Population) Secondary · Assessments every 8 weeks from C1D1 until disease progression, death, or initiation of subsequent treatment. After 18 months on study, assessments every 16 weeks. Total follow-up was up to approximately 3.5 years.

A secondary endpoint is the DOR for the Treatment Part of the study. The DOR as assessed by investigator is analyzed in the subgroup of patients who had a confirmed response by RECIST v1.1. DOR for any confirmed RECIST CR or PR will be measured from the date of the first response until the first date that progressive disease (PD) is documented. DOR is calculated in months as the time from the first date of the scan showing a response to the first scan with disease progression +1 day. Any patients with an ongoing response are censored at the date of the last post-baseline scan. Only tumor scans

GroupValue95% CI
Rucaparib9.47.5 – 11.1
Chemotherapy7.24.0 – 11.4
Investigator Assessed Duration of Response (DOR) by RECIST v1.1 (ITT Population) Secondary · Assessments every 8 weeks from C1D1 until disease progression, death, or initiation of subsequent treatment. After 18 months on study, assessments every 16 weeks. Total follow-up was up to approximately 3.5 years.

A secondary endpoint is the DOR for the Treatment Part of the study. The DOR as assessed by investigator is analyzed in the subgroup of patients who had a confirmed response by RECIST v1.1. DOR for any confirmed RECIST CR or PR will be measured from the date of the first response until the first date that progressive disease (PD) is documented. DOR is calculated in months as the time from the first date of the scan showing a response to the first scan with disease progression +1 day. Any patients with an ongoing response are censored at the date of the last post-baseline scan. Only tumor scans

GroupValue95% CI
Rucaparib9.47.5 – 11.1
Chemotherapy7.23.9 – 9.4
Investigator Assessed Overall Response Rate (ORR) by RECIST v1.1 and/or CA-125 Response (Efficacy Population) Secondary · Assessments every 8 weeks from C1D1 until disease progression, death, or initiation of subsequent treatment. After 18 months on study, assessments every 16 weeks. Total follow-up was up to approximately 3.5 years.

A secondary endpoint is ORR for the Treatment Part of the study defined as the percentage of patients with best response of CR or PR using RECIST v1.1 or response per Gynecologic Cancer InterGroup Cancer Antigen 125 (GCIG CA-125) criteria. Complete response (CR) is disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. Partial response (PR) is at least a 30% decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum of longest diameter. Response to CA-125 has occurre

GroupValue95% CI
Rucaparib50.743.8 – 57.5
Chemotherapy43.633.7 – 53.8
Investigator Assessed Overall Response Rate (ORR) by RECIST v1.1 and/or CA-125 Response (ITT Population) Secondary · Assessments every 8 weeks from C1D1 until disease progression, death, or initiation of subsequent treatment. After 18 months on study, assessments every 16 weeks. Total follow-up was up to approximately 3.5 years.

A secondary endpoint is ORR for the Treatment Part of the study defined as the percentage of patients with best response of CR or PR using RECIST v1.1 or response per Gynecologic Cancer InterGroup Cancer Antigen 125 (GCIG CA-125) criteria. Complete response (CR) is disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. Partial response (PR) is at least a 30% decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum of longest diameter. Response to CA-125 has occurre

GroupValue95% CI
Rucaparib47.841.2 – 54.5
Chemotherapy40.531.3 – 50.3
Least Squares Mean Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) Global Health Status Score for the First 6 Cycles (Efficacy Population) Secondary · Baseline to the end of Cycle 6, or up to approximately 6 months

EORTC QLQ-C30 is a questionnaire that rates the overall quality of life in cancer patients. The first 28 questions use a 4-point scale (1=not at all to 4=very much) for evaluating function (physical, role, social, cognitive, emotional), symptoms (diarrhea, fatigue, dyspnea, appetite loss, insomnia, nausea/vomiting, constipation, and pain) and financial difficulties. The last 2 questions use a 7-point scale (1=very poor to 7=excellent) to evaluate overall health and quality of life. Global scores are converted to a score of 0 to 100, with a higher score indicating improved health status. Mean c

GroupValue95% CI
Rucaparib0.5± 0.55
Chemotherapy0.3± 0.86
Least Squares Mean Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) Global Health Status Score for the First 6 Cycles (ITT Population) Secondary · Baseline to the end of Cycle 6, or up to approximately 6 months

EORTC QLQ-C30 is a questionnaire that rates the overall quality of life in cancer patients. The first 28 questions use a 4-point scale (1=not at all to 4=very much) for evaluating function (physical, role, social, cognitive, emotional), symptoms (diarrhea, fatigue, dyspnea, appetite loss, insomnia, nausea/vomiting, constipation, and pain) and financial difficulties. The last 2 questions use a 7-point scale (1=very poor to 7=excellent) to evaluate overall health and quality of life. Global scores are converted to a score of 0 to 100, with a higher score indicating improved health status. Mean c

GroupValue95% CI
Rucaparib0.6± 0.54
Chemotherapy0.4± 0.82
Overall Survival (Efficacy Population) Secondary · All patients were followed for survival up to approximately 3.5 years.

Overall survival (OS) is defined as the number of days from the date of randomization to the date of death (due to any cause). Patients who are still alive were censored on the date of their last available visit or last date known to be alive.

GroupValue95% CI
Rucaparib21.117.9 – 24.9
Chemotherapy26.222.2 – 29.1
Overall Survival (ITT Population) Secondary · All patients were followed for survival up to approximately 3.5 years.

Overall survival (OS) is defined as the number of days from the date of randomization to the date of death (due to any cause). Patients who are still alive were censored on the date of their last available visit or last date known to be alive.

GroupValue95% CI
Rucaparib19.415.2 – 23.6
Chemotherapy25.421.4 – 27.6

Adverse events — posted to ClinicalTrials.gov

Time frame: Adverse events were reported from date of first dose of study drug until 28 days after last dose of study drug, approximately 3.5 years.. Reporting threshold: 5%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Rucaparib (Treatment Part)
Serious: 66/232 (28%)
Deaths: 16/232
Chemotherapy (Treatment Part)
Serious: 14/113 (12%)
Deaths: 4/113
Rucaparib (Crossover Part)
Serious: 24/80 (30%)
Deaths: 3/80

Serious adverse events (85 terms)

ReactionSystemRucaparib (Treatment Part)Chemotherapy (Treatment Pa…Rucaparib (Crossover Part)
AnemiaBlood and lymphatic system disorders
Intestinal obstructionGastrointestinal disorders
Malignant neoplasm progressionNeoplasms benign, malignant and unspecified (incl cysts and polyps)
ThrombocytopeniaBlood and lymphatic system disorders
NeutropeniaBlood and lymphatic system disorders
VomitingGastrointestinal disorders
PneumoniaInfections and infestations
Myelodysplastic syndromeNeoplasms benign, malignant and unspecified (incl cysts and polyps)
Deep vein thrombosisVascular disorders
AscitesGastrointestinal disorders
DeathGeneral disorders
General physical health deteriorationGeneral disorders
SepsisInfections and infestations
Urinary tract infectionInfections and infestations
DehydrationMetabolism and nutrition disorders
Febrile neutropeniaBlood and lymphatic system disorders
LeukopeniaBlood and lymphatic system disorders
PancytopeniaBlood and lymphatic system disorders
Cardiac disorderCardiac disorders
Pericardial effusionCardiac disorders
Abdominal distensionGastrointestinal disorders
Abdominal painGastrointestinal disorders
ConstipationGastrointestinal disorders
DiarrhoeaGastrointestinal disorders
Dolichocolon acquiredGastrointestinal disorders
Other adverse events (69 terms — click to expand)

ReactionSystemRucaparib (Treatment Part)Chemotherapy (Treatment Pa…Rucaparib (Crossover Part)
AnaemiaBlood and lymphatic system disorders
NauseaGastrointestinal disorders
VomitingGastrointestinal disorders
Alanine aminotransferase increasedInvestigations
Aspartate aminotransferase increasedInvestigations
AstheniaGeneral disorders
FatigueGeneral disorders
Abdominal painGastrointestinal disorders
DiarrhoeaGastrointestinal disorders
NeutropeniaBlood and lymphatic system disorders
ThrombocytopeniaBlood and lymphatic system disorders
Decreased appetiteMetabolism and nutrition disorders
Blood creatinine increasedInvestigations
AlopeciaSkin and subcutaneous tissue disorders
ConstipationGastrointestinal disorders
DysgeusiaNervous system disorders
Weight decreasedInvestigations
DyspnoeaRespiratory, thoracic and mediastinal disorders
PyrexiaGeneral disorders
LeukopeniaBlood and lymphatic system disorders
Abdominal pain upperGastrointestinal disorders
Blood bilirubin increasedInvestigations
Urinary tract infectionInfections and infestations
InsomniaPsychiatric disorders
CoughRespiratory, thoracic and mediastinal disorders
DyspepsiaGastrointestinal disorders
Blood alkaline phosphatase increasedInvestigations
HyperglycaemiaMetabolism and nutrition disorders
HeadacheNervous system disorders
ArthralgiaMusculoskeletal and connective tissue disorders
Neuropathy peripheralNervous system disorders
Abdominal distensionGastrointestinal disorders
AscitesGastrointestinal disorders
HypomagnesaemiaMetabolism and nutrition disorders
Oedema peripheralGeneral disorders
DizzinessNervous system disorders
RashSkin and subcutaneous tissue disorders
Abdominal pain lowerGastrointestinal disorders
Intestinal obstructionGastrointestinal disorders
Back painMusculoskeletal and connective tissue disorders

Most-reported serious reactions: Anemia, Intestinal obstruction, Malignant neoplasm progression, Thrombocytopenia, Neutropenia, Vomiting, Pneumonia, Myelodysplastic syndrome.

Data from ClinicalTrials.gov NCT02855944 adverse events section.

Sponsor's own description

The purpose of this study is to determine how patients with ovarian, fallopian tube, and primary peritoneal cancer will best respond to treatment with rucaparib versus chemotherapy.

Publications & conference data

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

  1. Advances in ovarian cancer therapy.
    Cortez AJ, Tudrej P, Kujawa KA, Lisowska KM. · · 2018 · cited 417× · PMID 29249039 · DOI 10.1007/s00280-017-3501-8
  2. PARP inhibitors: Clinical utility and possibilities of overcoming resistance.
    Bitler BG, Watson ZL, Wheeler LJ, Behbakht K. · · 2017 · cited 161× · PMID 29037806 · DOI 10.1016/j.ygyno.2017.10.003
  3. PARP Inhibitors in Ovarian Cancer: A Review.
    O'Malley DM, Krivak TC, Kabil N, Munley J, et al · · 2023 · cited 128× · PMID 37268756 · DOI 10.1007/s11523-023-00970-w
  4. Rucaparib versus standard-of-care chemotherapy in patients with relapsed ovarian cancer and a deleterious BRCA1 or BRCA2 mutation (ARIEL4): an international, open-label, randomised, phase 3 trial.
    Kristeleit R, Lisyanskaya A, Fedenko A, Dvorkin M, et al · · 2022 · cited 123× · PMID 35298906 · DOI 10.1016/s1470-2045(22)00122-x
  5. Targeted therapies in gynecological cancers: a comprehensive review of clinical evidence.
    Wang Q, Peng H, Qi X, Wu M, et al · · 2020 · cited 114× · PMID 32728057 · DOI 10.1038/s41392-020-0199-6
  6. Portrait of a cancer: mutational signature analyses for cancer diagnostics.
    Van Hoeck A, Tjoonk NH, van Boxtel R, Cuppen E. · · 2019 · cited 85× · PMID 31092228 · DOI 10.1186/s12885-019-5677-2
  7. Targeting DNA repair pathway in cancer: Mechanisms and clinical application.
    Wang M, Chen S, Ao D. · · 2021 · cited 84× · PMID 34977872 · DOI 10.1002/mco2.103
  8. Advances and perspectives of PARP inhibitors.
    Yi M, Dong B, Qin S, Chu Q, et al · · 2019 · cited 83× · PMID 31737426 · DOI 10.1186/s40164-019-0154-9

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