A Study to Test the Benefit of a New Anti-cancer Treatment in Patients With Unresectable Advanced Melanoma

Melanoma Clinical Trial

— PREDICT  

Official title:

GSK2132231A Antigen-Specific Cancer Immunotherapeutic as First-line Treatment of Patients With Unresectable Metastatic Melanoma

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00942162
• Other study ID #: 111476
• Secondary ID: 2008-004007-64
• Status: Completed
• Phase: Phase 2
• Start date: August 14, 2009
• Est. completion date: April 1, 2015

Study information

• Verified date: December 2020
• Source: GlaxoSmithKline
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The objective of this study is to evaluate the clinical activity of the GSK2132231A immunotherapeutic in patients with MAGE-A3 positive unresectable metastatic melanoma presenting with the predictive gene signature.

Description:

In this study, patients were to receive a maximum of 24 doses of recMAGE-A3 + AS15 according four cycles over a period of four years. An active follow-phase (up to five years after registration into the study) was planned for all patients.

As of Amendment 2, there will no longer be an active follow-up of patients after discontinuation or completion of the treatment. The study will end approximately 30 days after the last dose will be administered.

In addition, no more biological samples will be collected for protocol research purposes. For each biological sample already collected in the scope of this study and not tested yet, testing will not be performed by default, except if a scientific rationale remains relevant.

Blood sampling for safety monitoring as per protocol will continue.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 125
• Est. completion date: April 1, 2015
• Est. primary completion date: June 27, 2012
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Male or female patients with histologically proven metastatic cutaneous melanoma that is measurable.

• Patients with regional or distant cutaneous, subcutaneous or lymph-node metastasis can be included in the study, provided the disease is not amenable to curative treatment with surgery. In terms of the AJCC 2002 classification, this includes patients with unresectable stage III melanoma including in-transit metastases or patient with stage IV M1a melanoma.

• Written informed consent obtained from the patient prior to performance of any study specific procedure.

• Patient is >= 18 years at the time of signature of the informed consent form.

• The patient's tumor shows expression of MAGE-A3, as determined by RT-PCR analysis on a fresh tumor tissue sample obtained during the screening phase.

• Fresh tissue from the same lesion as used for MAGE-A3 expression testing must be available for the testing of the predictive gene signature.

• Formalin-fixed paraffin-embedded (FFPE) tissue must be available for complementary MAGE-A3 and gene signature testing.

• Patient fully recovered from any previous intervention (i.e., biopsy).

• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

• Adequate bone-marrow reserve, adequate renal function and adequate hepatic function as assessed by standard laboratory criteria

• If the patient is female, she must be of non-childbearing potential, or if she is of childbearing potential, she must practice adequate contraception for at least 30 days prior to registration in the trial, have a negative pregnancy test and continue such precautions during the entire study treatment period and for 2 months after completion of the injection series.

• In the opinion of the investigator, the patient can and will comply with the protocol requirements.

Exclusion Criteria:

• Patients with unresectable stage IV M1b,c melanoma and patients with ocular and mucosal melanoma.

• The patient has at any time received any systemic anticancer treatment.

• Prior systemic treatment with an immunomodulator or loco-regional radiotherapy is permitted as prior adjuvant treatment provided that the last dose was administered at least 30 days before the registration into this trial;

• Previous adjuvant treatment with a cancer vaccine containing a tumor antigen other than MAGE-A3 is allowed if the last administration took place at least 8 weeks before registration into the trial.

• Prior isolated limb perfusion is permitted provided that the last dose was administered at least 30 days before registration into this trial

• The patient is scheduled to receive any anti-cancer specific treatment, including radiotherapy, other immunotherapy, chemotherapy and immunomodulating agents.

• The patient requires concomitant chronic treatment (more than 7 consecutive days) with systemic corticosteroids, or any other immunosuppressive agents.

• The patient has a history of autoimmune disease such as, but not limited to, multiple sclerosis, lupus, and inflammatory bowel disease. Patients with vitiligo are not excluded.

• The patient has a family history of congenital or hereditary immunodeficiency.

• The patient is known to be positive for Human Immunodeficiency Virus (HIV).

• History of allergic disease or reactions likely to be exacerbated by any component of the ASCI treatment.

• The patient has previous or concomitant malignancies at other sites, except effectively treated non-melanoma skin cancer or carcinoma in situ of the cervix and effectively treated malignancy that has been in remission for over 5 years and is highly likely to have been cured.

• The patient has psychiatric or addictive disorders

• The patient has an uncontrolled bleeding disorder.

• The patient has concurrent severe medical problems, unrelated to the malignancy, that would significantly limit full compliance with the study or expose the patient to unacceptable risk.

• Use of any investigational or non-registered product (drug or vaccine) other than the study medication within the 30 days preceding the first investigational treatment injection or planned use during the study period.

• Concurrently participating in another clinical study, at any time during the study period, in which the patient has been or will be exposed to an investigational or a non-investigational product (pharmaceutical product or device). For female patients: the patient is pregnant or lactating.

Related Conditions & MeSH terms

• Melanoma

Intervention

Biological:
• Immunotherapeutic GSK2132231A
Intramuscular administration

Locations

Country	Name	City	State
France	GSK Investigational Site	Besançon cedex
France	GSK Investigational Site	Boulogne
France	GSK Investigational Site	Brest
France	GSK Investigational Site	Dijon
France	GSK Investigational Site	Grenoble
France	GSK Investigational Site	Marseille Cedex 5
France	GSK Investigational Site	Montpellier
France	GSK Investigational Site	Nantes
France	GSK Investigational Site	Paris
France	GSK Investigational Site	Paris
France	GSK Investigational Site	Rouen
France	GSK Investigational Site	Tours
Germany	GSK Investigational Site	Berlin
Germany	GSK Investigational Site	Buxtehude	Niedersachsen
Germany	GSK Investigational Site	Erfurt	Thueringen
Germany	GSK Investigational Site	Essen	Nordrhein-Westfalen
Germany	GSK Investigational Site	Hannover	Niedersachsen
Germany	GSK Investigational Site	Heidelberg	Baden-Wuerttemberg
Germany	GSK Investigational Site	Homburg	Saarland
Germany	GSK Investigational Site	Jena	Thueringen
Germany	GSK Investigational Site	Kiel	Schleswig-Holstein
Germany	GSK Investigational Site	Koeln	Nordrhein-Westfalen
Germany	GSK Investigational Site	Ludwigshafen	Rheinland-Pfalz
Germany	GSK Investigational Site	Luebeck	Schleswig-Holstein
Germany	GSK Investigational Site	Mannheim	Baden-Wuerttemberg
Germany	GSK Investigational Site	Marburg	Hessen
Germany	GSK Investigational Site	Muenster	Nordrhein-Westfalen
Germany	GSK Investigational Site	Nuernberg	Bayern
Germany	GSK Investigational Site	Quedlinburg	Sachsen-Anhalt
Germany	GSK Investigational Site	Tuebingen	Baden-Wuerttemberg
Germany	GSK Investigational Site	Wiesbaden	Hessen
Germany	GSK Investigational Site	Wuerzburg	Bayern
Ireland	GSK Investigational Site	Cork
Ireland	GSK Investigational Site	Dublin
Ireland	GSK Investigational Site	Dublin
Ireland	GSK Investigational Site	Galway
Italy	GSK Investigational Site	Milano	Lombardia
Italy	GSK Investigational Site	Napoli	Campania
Italy	GSK Investigational Site	Padova	Veneto
Italy	GSK Investigational Site	Siena	Toscana
Poland	GSK Investigational Site	Kraków
Poland	GSK Investigational Site	Olsztyn
Poland	GSK Investigational Site	Poznan
Poland	GSK Investigational Site	Warszawa
Russian Federation	GSK Investigational Site	Moscow
Russian Federation	GSK Investigational Site	St. Petersburg
Spain	GSK Investigational Site	Barcelona
Spain	GSK Investigational Site	Madrid
United States	GSK Investigational Site	Ann Arbor	Michigan
United States	GSK Investigational Site	Chicago	Illinois
United States	GSK Investigational Site	Dallas	Texas
United States	GSK Investigational Site	Durham	North Carolina
United States	GSK Investigational Site	Houston	Texas
United States	GSK Investigational Site	Los Angeles	California
United States	GSK Investigational Site	Los Angeles	California
United States	GSK Investigational Site	Morristown	New Jersey
United States	GSK Investigational Site	Orange	California
United States	GSK Investigational Site	Orlando	Florida
United States	GSK Investigational Site	Philadelphia	Pennsylvania
United States	GSK Investigational Site	Saint Louis	Missouri
United States	GSK Investigational Site	Seattle	Washington
United States	GSK Investigational Site	Stuart	Florida
United States	GSK Investigational Site	Tampa	Florida

Sponsors (1)

Lead Sponsor	Collaborator
GlaxoSmithKline

Countries where clinical trial is conducted

United States,  France,  Germany,  Ireland,  Italy,  Poland,  Russian Federation,  Spain, 

References & Publications (1)

Saiag P, Gutzmer R, Ascierto PA, Maio M, Grob JJ, Murawa P, Dreno B, Ross M, Weber J, Hauschild A, Rutkowski P, Testori A, Levchenko E, Enk A, Misery L, Vanden Abeele C, Vojtek I, Peeters O, Brichard VG, Therasse P. Prospective assessment of a gene signature potentially predictive of clinical benefit in metastatic melanoma patients following MAGE-A3 immunotherapeutic (PREDICT). Ann Oncol. 2016 Oct;27(10):1947-53. doi: 10.1093/annonc/mdw291. Epub 2016 Aug 8. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	One-year Overall Survival Rate (OSR) Estimated by Complete Case Method	The 1-year overall survival rate (OSR) in the GS+ Population would be above 50% (target = 71%), a percentage which was reported together with its 95% confidence interval (CI). Maximum 1-year OSR of any currently available treatment in the MAGE-A3-positive population = 50% (P0). This median OS of 12 months is based on the observed median OS for MAGE-A3-positive patients, whose tumor did not present the predictive GS. The target 1-year OSR for patients presenting the predictive GS = 71% (P1). This corresponds to a median OS of 24 months when assuming an exponential distribution of OS.	Month 0 - Month 12
Primary	Number of Patients Reported With Serious Adverse Events (SAEs)	Serious adverse events (SAEs) assessed included medical occurrences that result in death, are life threatening, require hospitalization or prolongation of hospitalization or result in disability/ incapacity. Events which were part of the natural course of the disease under study (i.e., disease progression, recurrence) were captured as part of the clinical activity outcome variables in this study; therefore these did not need to be reported as SAEs. Progression/recurrence of the tumor in a patient was recorded as part of the clinical assessment data collection, and deaths due to progressive disease was recorded on a specific form, but not as an SAE. However, if the investigator considered that there was a causal relationship between treatment or protocol design/procedures and the disease progression/recurrence, then the event was reported as an SAE. Any new primary cancer (non-related to the cancer under study) was reported as an SAE.	Month 0 - Month 49
Secondary	Number of Patients With Diseases Characteristics by GS	Cancer staging (characteristics and categories) as by the categorization by the American Joint Committee on Cancer (AJCC) Staging Manual 2002: "Stage IIIA patients have up to three microscopic nodal metastases arising from a non-ulcerating primary melanoma and have an ' intermediate risk' for distant metastases and melanom-specific survival. Stage IIIB patients have up to three microscopic nodal metastases arising from a non-ulcerating melanoma or have up to three microscopic nodal metastases arising from an ulcerating melanoma, or have intralymphatic metastases without nodal metastases. They constitute a 'high-risk' group prognostically." The remaining patients with regional melanoma are Stage IIIC patients are at 'very high risk' for distant metastases and melanoma-specific mortality. Stage IV melanoma patients have metastasis at any distant site and constitute the group with the worst prognosis. Stage MC patients are those with confirmed missing cancer.	Month 0 - Month 49
Secondary	Progression-free Survival (PFS) by GS	From study start (Month 0) to Month 24, each patient was censored out of the analysis at 1st report of disease progression or death. PFS was defined and calculated as the time from first treatment to either the first progression of the disease or the date of death, whichever occurred first. In case a patient went off protocol treatment, the date of first documented progression (if applicable) was to be used as date of progression. Patients still alive with no evidence of disease progression at the time of their last visit or for whom date of first documented progression was not applicable, were censored at the time of the last examination. PFS analysis was performed using the non-parametric Kaplan-Meier method.	Month 0 - Month 24
Secondary	Kaplan-Meier Estimates of the Progression-free Survival (PFS) at Months 6, 12 and 24, by Gene Signature	PFS was defined as the time from the date of registration of the patient to either the date of disease progression or the date of death, whichever comes first. Patients alive and without disease progression were censored at the date of their last tumor evaluation. The PFS estimates were assessed by the Kaplan-Meier method and expressed as the percentage of patients who did not progress and were alive at a given time.	Month 6, Month 12, Month 24
Secondary	Overall Survival (OS) by GS	OS was defined as the time from registration of the patient until death, with patients alive at the time of analysis censored at the time of the last contact.	Up to 5 years from the time of registration.
Secondary	Time to Treatment Failure (TTF) by GS	The TTF was defined as the time from registration of the patient until the date of the last treatment administration, irrespective of the reason for study treatment discontinuation.	Month 0 - Month 24
Secondary	Best Overall Response (BOR) by GS	The BOR was the best response recorded from the start of the treatment until disease progression/ recurrence, except for confirmed objective response, which was reported as BOR independently of its time of occurrence. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI and/or CT: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions without any new lesions and/or progression of existing non-target lesions; Stable Disease (SD), neither sufficient shrinkage to qualify for a Partial Response nor sufficient increase to qualify for Progression of Disease (PD) without any new lesions and/or progression of existing non-target lesions; PD, >=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; NE = Non-evaluable response.	Month 0 - Month 24
Secondary	Duration of Response (CR or PR)	Duration of response was measured from the time when the measurement criteria for CR/ PR (whichever was recorded first) were met until the first date that recurrent or PD was objectively documented (taking as reference for PD the smallest measurements recorded since the treatment started). Note: As there was only one patient analysed in the GSK2132231A GS- Group, the median duration of response was not calculated for this latter group.	Month 0 - Month 24
Secondary	Duration of Stable Disease (SD), or Time-to-Progression (TTP) by GS	The duration of stable disease (SD), or TTP, was tabulated for patients whose best response was SD. The minimal time interval required between 2 measurements for determination of SD was 12 weeks.	Month 0 - Month 24
Secondary	Number of Seropositive Patients for Anti-MAGE-A3	Seropositive patients were those patients with anti-MAGE-A3 antibody concentrations = 27 enzyme-linked immunosorbent assay (ELISA) units per milliliter (EL.U/mL).	PRE = Pre any dose, PII(W4) = Post-Dose 2 (Week 4), PVI(W12) = Post-Dose 6 (Week 12), PXII(W31) = Post-Dose 12 (Week 31), PXVI(W54) = Post-Dose 16 (Week 54), PXVII(M18) = Post-Dose 17 (Month 18), PXXIV(M49) = Post-Dose 24 (Month 49).
Secondary	Anti-MAGE-A3 Antibody Concentrations	Anti-MAGE-A3 antibody concentrations were presented as geometric mean concentrations (GMCs) and expressed in EL.U/mL.	PRE = Pre any dose, PII(W4) = Post-Dose 2 (Week 4), PVI(W12) = Post-Dose 6 (Week 12), PXII(W31) = Post-Dose 12 (Week 31), PXVI(W54) = Post-Dose 16 (Week 54), PXVII(M18) = Post-Dose 17 (Month 18), PXXIV(M49) = Post-Dose 24 (Month 49)
Secondary	Number of Seropositive Patients for Protein D	Seropositive patients were those patients with anti-PD antibody concentrations = 100 EL.U/mL.	PRE = Pre any dose, PII(W4) = Post-Dose 2 (Week 4), PVI(W12) = Post-Dose 6 (Week 12), PXII(W31) = Post-Dose 12 (Week 31), PXVI(W54) = Post-Dose 16 (Week 54), PXVII(M18) = Post-Dose 17 (Month 18), PXXIV(M49) = Post-Dose 24 (Month 49)
Secondary	Concentrations of Antibodies Against Protein D (Anti-PD)	Anti-PD antibody concentrations were presented as geometric mean concentrations (GMCs) and expressed in EL.U/mL.	PRE = Pre any dose, PII(W4) = Post-Dose 2 (Week 4), PVI(W12) = Post-Dose 6 (Week 12), PXII(W31) = Post-Dose 12 (Week 31), PXVI(W54) = Post-Dose 16 (Week 54), PXVII(M18) = Post-Dose 17 (Month 18), PXXIV(M49) = Post-Dose 24 (Month 49)
Secondary	Anti-MAGE-A3 Antibody Response	Anti-MAGE-A3 antibody response defined as: For initially seronegative patients: post-vaccination antibody concentration = 27 EL.U/mL; For initially seropositive patients: post-vaccination antibody concentration = 2 fold the pre-vaccination antibody concentration.	PII(W4) = Post-Dose 2 (Week 4), PVI(W12) = Post-Dose 6 (Week 12), PXII(W31) = Post-Dose 12 (Week 31), PXVI(W54) = Post-Dose 16 (Week 54), PXVII(M18) = Post-Dose 17 (Month 18), PXXIV(M49) = Post-Dose 24 (Month 49)
Secondary	Anti-PD Antibody Response	Anti-PD antibody response defined as: For initially seronegative patients: post-vaccination antibody concentration = 100 EL.U/mL; For initially seropositive patients: post-vaccination antibody concentration = 2 fold the pre-vaccination antibody concentration.	PII(W4) = Post-Dose 2 (Week 4), PVI(W12) = Post-Dose 6 (Week 12), PXII(W31) = Post-Dose 12 (Week 31), PXVI(W54) = Post-Dose 16 (Week 54), PXVII(M18) = Post-Dose 17 (Month 18), PXXIV(M49) = Post-Dose 24 (Month 49)
Secondary	Number of Patients With Abnormal Alanine Aminotransferase (ALT) Values by Maximum Grade	The status of each patient as regards ALT laboratory values at baseline (SCR) up to study end (SE) was collected and graded according to the Common Terminology Criteria (CTC) Adverse event terminology, version 3.0. The post-treatment values were presented by worst grade versus baseline grade. SCR CTC grade statuses reported were Grade 0 (G0) and G1. CTC grade statuses reported at SE were G0, G1, G2, G3 and Unknown (UNK).	Month 0 - Month 49 (each patient was censored out of the analysis at time of death)
Secondary	Number of Patients With Abnormal Aspartate Aminotransferase (AST) Values by Maximum Grade	The status of each patient as regards AST laboratory values at baseline (SCR) up to study end (SE) was collected and graded according to the Common Terminology Criteria (CTC) Adverse event terminology, version 3.0. The post-treatment values were presented by worst grade versus baseline grade. SCR CTC grade statuses reported were Grade 0 (G0) and G1. CTC grade statuses reported at SE were G0, G1 and Unknown (UNK).	Month 0 - Month 49 (each patient was censored out of the analysis at time of death)
Secondary	Number of Patients With Abnormal Alkaline Phosphatase (ALK) Values by Maximum Grade	The status of each patient as regards ALK laboratory values at baseline (SCR) up to study end (SE) was collected and graded according to the Common Terminology Criteria (CTC) Adverse event terminology, version 3.0. The post-treatment values were presented by worst grade versus baseline grade. SCR CTC grade statuses reported were Grade 0 (G0) and G1. CTC grade statuses reported at SE were G0, G1 and Unknown (UNK).	Month 0 - Month 49 (each patient was censored out of the analysis at time of death)
Secondary	Number of Patients With Abnormal Bilirubine (BIL) Values by Maximum Grade	The status of each patient as regards BIL laboratory values at baseline (SCR) up to study end (SE) was collected and graded according to the Common Terminology Criteria (CTC) Adverse event terminology, version 3.0. The post-treatment values were presented by worst grade versus baseline grade. SCR CTC grade statuses reported were Grade 0 (G0), G1 and G2. CTC grade statuses reported at SE were G0, G1, G2 and Unknown (UNK).	Month 0 - Month 49 (each patient was censored out of the analysis at time of death)
Secondary	Number of Patients With Abnormal Creatinine (CREA) Values by Maximum Grade	The status of each patient as regards CREA laboratory values at baseline (SCR) up to study end (SE) was collected and graded according to the Common Terminology Criteria (CTC) Adverse event terminology, version 3.0. The post-treatment values were presented by worst grade versus baseline grade. SCR CTC grade statuses reported were Grade 0 (G0), G1 and G2. CTC grade statuses reported at SE were G0, G1, G2 and Unknown (UNK).	Month 0 - Month 49 (each patient was censored out of the analysis at time of death)
Secondary	Number of Patients With Abnormal Hemoglobin (HGB) Values by Maximum Grade	The status of each patient as regards HGB laboratory values at baseline (SCR) up to study end (SE) was collected and graded according to the Common Terminology Criteria (CTC) Adverse event terminology, version 3.0. The post-treatment values were presented by worst grade versus baseline grade. SCR CTC grade statuses reported were Grade 0 (G0), G1 and G2. CTC grade statuses reported at SE were G0, G1, G2, G3, G4, and Unknown (UNK).	Month 0 - Month 49 (each patient was censored out of the analysis at time of death)
Secondary	Number of Patients With Abnormal Leukocytes (LEU) Values by Maximum Grade	The status of each patient as regards LEU laboratory values at baseline (SCR) up to study end (SE) was collected and graded according to the Common Terminology Criteria (CTC) Adverse event terminology, version 3.0. The post-treatment values were presented by worst grade versus baseline grade. SCR CTC grade statuses reported were Grade 0 (G0), G1 and G2. CTC grade statuses reported at SE were G0, G1, G2, G4, and Unknown (UNK).	Month 0 - Month 49 (each patient was censored out of the analysis at time of death)
Secondary	Number of Patients With Abnormal Lymphopenia (LYM) Values by Maximum Grade	The status of each patient as regards LYM laboratory values at baseline (SCR) up to study end (SE) was collected and graded according to the Common Terminology Criteria (CTC) Adverse event terminology, version 3.0. The post-treatment values were presented by worst grade versus baseline grade. SCR CTC grade statuses reported were Grade 0 (G0), G1, G2 and G3. CTC grade statuses reported at SE were G0, G1, G2, G3 and Unknown (UNK).	Month 0 - Month 49 (each patient was censored out of the analysis at time of death)
Secondary	Number of Patients With Abnormal Neutrophils (NEU) Values by Maximum Grade	The status of each patient as regards NEU laboratory values at baseline (SCR) up to study end (SE) was collected and graded according to the Common Terminology Criteria (CTC) Adverse event terminology, version 3.0. The post-treatment values were presented by worst grade versus baseline grade. SCR CTC grade statuses reported were Grade 0 (G0), G1 and G2. CTC grade statuses reported at SE were G0, G1, G2, G3 and Unknown (UNK).	Month 0 - Month 49 (each patient was censored out of the analysis at time of death)
Secondary	Number of Patients With Abnormal Platelets (PLT) Values by Maximum Grade	The status of each patient as regards PLT laboratory values at baseline (SCR) up to study end (SE) was collected and graded according to the Common Terminology Criteria (CTC) Adverse event terminology, version 3.0. The post-treatment values were presented by worst grade versus baseline grade. SCR CTC grade statuses reported were Grade 0 (G0) and G1. CTC grade statuses reported at SE were G0, G1, G4, and Unknown (UNK).	Month 0 - Month 49 (each patient was censored out of the analysis at time of death)
Secondary	Number of Patients With Autoimmune Diseases or Immune-mediated Inflammatory Disorders	Auto-immune diseases or immune-mediated inflammatory disorders were tabulated during the whole duration of the study (up to 30 days after the last administration of the study treatment). The results were tabulated as Any event(s) reported.	Month 0 - Month 49
Secondary	Number of Patients Reported With Unsolicited Adverse Events (AEs) by Maximum Grade.	The assessed AEs were ASCI-related adverse events according to the Common Terminology Criteria for Adverse Events (CTCAE) version 3.0. Grade 1 = Mild AE; Grade 2 = Moderate AE; Grade 3 = Severe AE; Grade 4 = Life-threatening or disabling AE; Grade 5 = Death due to AE. An unsolicited AE covers any untoward medical occurrence in a clinical investigation patient temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product and reported in addition to those solicited during the clinical study and any solicited symptom with onset outside the specified period of follow-up for solicited symptoms.	Through 30 days after the last administration of the study treatment, approximately 49 months
Secondary	Number of Patients Reported With Unsolicited AE(s)	An unsolicited AE covers any untoward medical occurrence in a clinical investigation patient temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product and reported in addition to those solicited during the clinical study and any solicited symptom with onset outside the specified period of follow-up for solicited symptoms.	Through 30 days after the last administration of the study treatment, approximately 49 months

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