Evaluation of a New Vaccine Treatment for Patients With Metastatic Skin Cancer

An unsolicited AE covers any untoward medical occurrence in a clinical investigation subject 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. Any was defined as the occurrence of any unsolicited AE regardless of intensity grade or relation to vaccination. The grading to be used by the investigators for the assessment of the severity of adverse events (AEs) was defined as the Common Terminology Criteria for Adverse Events (CTCAE), Version 4.0 (Grade 1 = mild; Grade 2 = moderate; Grade 3 = severe or medically significant; Grade 4 = life-threatening; Grade 5 = death related to AE). Adverse Events were coded to the preferred term (PT) level by means of the Medical Dictionary for Regulatory Activities (MedDRA).

Serious adverse events (SAEs) assessed include medical occurrences that result in death, are life threatening, require hospitalization or prolongation of hospitalization or result in disability/incapacity. The grading to be used by the investigators for the assessment of the severity of adverse events (AEs) was defined as the Common Terminology Criteria for Adverse Events (CTCAE), Version 4.0 (Grade 1 = mild; Grade 2 = moderate; Grade 3 = severe or medically significant; Grade 4 = life-threatening; Grade 5 = death related to AE). SAEs were coded to the preferred term (PT) level by means of the Medical Dictionary for Regulatory Activities (MedDRA).

Laboratory abnormalities belong to hematological and biochemical parameters such as: activated partial thromboplastin time prolonged [APTTP], alanine aminotransferase increased [ALT/I], alkaline phoshatase increased [APH/I], anemia [AN], asparatate aminostransferase increased [AST/I], blood bilirubin increased [BB/I], creatinine increased [CRE/I], gamma glumatymtransferase increased [GGT/I], hemoglobin increased [Hgb/I], hypoalbuminemia [HYP], lymphocyte count decreased [LYMC/D], lymphocyte count increased [LYMC/I], neutrophil count decreased [ NEUC/D], platelet count decreased [PLA/D], white blood cell decreased [WBC/D]. Parameter grades (G0,1,2,3,4,Unknown) were compared to each baseline parameter grade (GUnknown,0,1,2,3), as defined by the Common Terminology Criteria for Adverse Events (CTCAE), version 4.0 of May 28, 2009 [http://evs.nci.nih.gov/ftp1/CTCAE]. This endpoint presents values for [APTTP] grading versus baseline parameter grading.

Laboratory abnormalities belong to hematological and biochemical parameters such as: activated partial thromboplastin time prolonged [APTTP], alanine aminotransferase increased [ALT/I], alkaline phoshatase increased [APH/I], anemia [AN], asparatate aminostransferase increased [AST/I], blood bilirubin increased [BB/I], creatinine increased [CRE/I], gamma glumatymtransferase increased [GGT/I], hemoglobin increased [Hgb/I], hypoalbuminemia [HYP], lymphocyte count decreased [LYMC/D], lymphocyte count increased [LYMC/I], neutrophil count decreased [ NEUC/D], platelet count decreased [PLA/D], white blood cell decreased [WBC/D]. Parameter grades (G0,1,2,3,4,Uknown) were compared to each baseline parameter grade (GUnknown,0,1,2,3), as defined by the Common Terminology Criteria for Adverse Events (CTCAE), version 4.0 of May 28, 2009 [http://evs.nci.nih.gov/ftp1/CTCAE]. This endpoint presents values for [ALT/I] and [APH/I] grading versus baseline parameter grading.

Laboratory abnormalities belong to hematological and biochemical parameters such as: activated partial thromboplastin time prolonged [APTTP], alanine aminotransferase increased [ALT/I], alkaline phoshatase increased [APH/I], anemia [AN], asparatate aminostransferase increased [AST/I], blood bilirubin increased [BB/I], creatinine increased [CRE/I], gamma glumatymtransferase increased [GGT/I], hemoglobin increased [Hgb/I], hypoalbuminemia [HYP], lymphocyte count decreased [LYMC/D], lymphocyte count increased [LYMC/I], neutrophil count decreased [ NEUC/D], platelet count decreased [PLA/D], white blood cell decreased [WBC/D]. Parameter grades (G0,1,2,3,4,Uknown) were compared to baseline parameter grades (GUnknown,0,1,2,3), as defined by the Common Terminology Criteria for Adverse Events (CTCAE), version 4.0 of May 28, 2009 [http://evs.nci.nih.gov/ftp1/CTCAE]. This endpoint presents values for [AN], [AST/I] and [CRE/I] grading versus baseline parameter grading.

Laboratory abnormalities belong to hematological and biochemical parameters such as: activated partial thromboplastin time prolonged [APTTP], alanine aminotransferase increased [ALT/I], alkaline phoshatase increased [APH/I], anemia [AN], asparatate aminostransferase increased [AST/I], blood bilirubin increased [BB/I], creatinine increased [CRE/I], gamma glumatymtransferase increased [GGT/I], hemoglobin increased [Hgb/I], hypoalbuminemia [HYP], lymphocyte count decreased [LYMC/D], lymphocyte count increased [LYMC/I], neutrophil count decreased [ NEUC/D], platelet count decreased [PLA/D], white blood cell decreased [WBC/D]. Parameter grades (G0,1,2,3,4,Uknown) were compared to baseline parameter grades (GUnknown,0,1,2,3), as defined by the Common Terminology Criteria for Adverse Events (CTCAE), version 4.0 of May 28, 2009 [http://evs.nci.nih.gov/ftp1/CTCAE]. This endpoint presents values for [CRE/I] and [GGT/I] grading versus baseline parameter grading.

Laboratory abnormalities belong to hematological and biochemical parameters such as: activated partial thromboplastin time prolonged [APTTP], alanine aminotransferase increased [ALT/I], alkaline phoshatase increased [APH/I], anemia [AN], asparatate aminostransferase increased [AST/I], blood bilirubin increased [BB/I], creatinine increased [CRE/I], gamma glumatymtransferase increased [GGT/I], hemoglobin increased [Hgb/I], hypoalbuminemia [HYP], lymphocyte count decreased [LYMC/D], lymphocyte count increased [LYMC/I], neutrophil count decreased [ NEUC/D], platelet count decreased [PLA/D], white blood cell decreased [WBC/D]. Parameter grades (G0,1,2,3,4,Uknown) were compared to each baseline parameter grade (GUnknown,0,1,2,3), as defined by the Common Terminology Criteria for Adverse Events (CTCAE), version 4.0 of May 28, 2009 [http://evs.nci.nih.gov/ftp1/CTCAE]. This endpoint presents values for [Hgb/I] and [HYP] grading versus baseline parameter grading.

Laboratory abnormalities belong to hematological and biochemical parameters such as: activated partial thromboplastin time prolonged [APTTP], alanine aminotransferase increased [ALT/I], alkaline phoshatase increased [APH/I], anemia [AN], asparatate aminostransferase increased [AST/I], blood bilirubin increased [BB/I], creatinine increased [CRE/I], gamma glumatymtransferase increased [GGT/I], hemoglobin increased [Hgb/I], hypoalbuminemia [HYP], lymphocyte count decreased [LYMC/D], lymphocyte count increased [LYMC/I], neutrophil count decreased [ NEUC/D], platelet count decreased [PLA/D], white blood cell decreased [WBC/D]. Parameter grades (G0,1,2,3,4,Uknown) were compared to each baseline parameter grade (GUnknown,0,1,2,3), as defined by the Common Terminology Criteria for Adverse Events (CTCAE), version 4.0 of May 28, 2009 [http://evs.nci.nih.gov/ftp1/CTCAE]. This endpoint presents values for [LYMC/D] and [LYMC/I] grading versus baseline parameter grading.

Laboratory abnormalities belong to hematological and biochemical parameters such as: activated partial thromboplastin time prolonged [APTTP], alanine aminotransferase increased [ALT/I], alkaline phoshatase increased [APH/I], anemia [AN], asparatate aminostransferase increased [AST/I], blood bilirubin increased [BB/I], creatinine increased [CRE/I], gamma glumatymtransferase increased [GGT/I], hemoglobin increased [Hgb/I], hypoalbuminemia [HYP], lymphocyte count decreased [LYMC/D], lymphocyte count increased [LYMC/I], neutrophil count decreased [NEUC/D], platelet count decreased [PLA/D], white blood cell decreased [WBC/D]. Parameter grades (G0,1,2,3,4,Uknown) were compared to each baseline parameter grades (GUnknown,0,1,2,3), as defined by the Common Terminology Criteria for Adverse Events (CTCAE), version 4.0 of May 28, 2009 [http://evs.nci.nih.gov/ftp1/CTCAE]. This endpoint presents values for [NEUC/D], [PLA/D] and [WBC/D] grading versus baseline parameter grading.

Cellular response was defined as: Geometric Mean Response (GMR) above the 2.68 cut-off value and at least a four-fold increase of PRAME- specific Cluster of Differentiation (CD) 4/8 T-cells. Considering that 2 studies failed to demonstrate clinical efficacy of recombinant protein based cancer vaccines, GSK decided in 2014 to stop the development and to stop recruitment in all the ongoing clinical studies. The decision was made to end the study (i.e., stopping patient enrollment, follow-ups, sample collection and analysis of samples for research purposes). Patients still on treatment at the time of the protocol amendment were offered to continue the administration of the study treatment until the last dose or until recurrence, whichever came first, or until the patient or the investigator decided to stop the study treatment. No further active protocol visit/contact was performed except for the concluding visit at Week 199, 30 days after the last treatment administration.

A seropositive patient was a patient whose anti-PRAME antibody concentration was greater than or equal to (≥) the assay cut-off value of 12 ELISA units per milliliter (EL.U/mL). A seronegative patient was defined as a patient whose pre-treatment antibody concentration was below (<) the cut-off value. An anti-PRAME antibody responder was defined as: For a seronegative patient: a post-treatment antibody concentration ≥ the cut-off value; For a seropositive patient: a post-treatment antibody concentration ≥ twice the pre-treatment antibody concentration.

Tumor response was assessed by the Response Evaluation Criteria In Solid Tumors (RECIST), where stable disease for target lesions refers to neither enough shrinkage to qualify for complete response nor sufficient increase to qualify for progressive disease taking as references the smallest sum longest diameter (LD) since the treatment started. For non-targeted lesions it refers to persistence of one or more non-target lesions. Progressive disease is related to a clear increase of diameters of lesions taking as references the smallest diameters recorded since the treatment started OR the appearance of one or more new lesions OR both of these.

Tumor response was assessed by the RECIST criteria, where SD for target lesions refers to neither enough shrinkage to qualify for CR nor sufficient increase to qualify for PD taking as references the smallest sum longest diameter (LD) since the treatment started. For non-targeted lesions it refers to persistence of one or more nom-target lesions. Progressive disease is related to a clear increase of diameters of lesions taking as references the smallest diameters recorded since the treatment started OR the appearance of one or more new lesions OR both of these. Mixed response is defined as at least 30% decrease in the LD occurring in at least one target lesion recorded and measured at baseline. Such response occurring in otherwise SD or PD status of the LD of target lesions were classified as "SD with target lesion regression" or "PD with target lesion regression", respectively. New lesion(s) in otherwise PR status of the LD of target lesions were "PR with new lesion".

Analysis of immunogenicity for anti-PD antibodies was not performed, following negative results to the NCT00480025 study which assessed another study product from same technology platform. For this study, the main analysis of the dose-escalation Phase I segment was performed according to protocol when all patients enrolled in the Phase I segment had received the first 4 treatment doses and had completed Week 8. The main analysis of the Phase II segment was performed according to protocol when all patients had either completed the treatment until the end of Cycle 3 or had been withdrawn from the study treatment, with the exception of anti-PD antibody responses and PRAME-specific cellular responses which were not yet performed. All samples that had been collected but not yet tested were not tested by default, except if a scientific rationale remained relevant.

Analysis of immunogenicity for anti-CpG antibodies was not performed, following negative results to the NCT00480025 study which assessed another study product from same technology platform. For this study, the main analysis of the dose-escalation Phase I segment was performed according to protocol when all patients enrolled in the Phase I segment had received the first 4 treatment doses and had completed Week 8. The main analysis of the Phase II segment was performed according to protocol when all patients had either completed the treatment until the end of Cycle 3 or had been withdrawn from the study treatment, with the exception of anti-CpG antibody responses and PRAME-specific cellular responses which were not yet performed. All samples that had been collected but not yet tested were not tested by default, except if a scientific rationale remained relevant.

Time to treatment failure (TTF) was defined as the time from first administration of study product until the date of the last administration of the product, irrespective of the reason for study treatment discontinuation. Progression-free survival (PFS) was defined as the time from first adminsitration of study product until the date of either disease progression or death (for whatever reason), whichever comes first. Overall survival (OS) was defined as the time from first administration of study product until death.

This analysis was not performed following negative results to the NCT00480025 study which assessed another study product from same technology platform. For this study, the main analysis of the dose-escalation Phase I segment was performed according to protocol when all patients enrolled in the Phase I segment had received the first 4 treatment doses and had completed Week 8. The main analysis of the Phase II segment was performed according to protocol when all patients had either completed the treatment until the end of Cycle 3 or had been withdrawn from the study treatment, with the exception of anti-CpG/anti-PD antibody responses and PRAME-specific cellular responses which were not yet performed. All samples that had been collected but not yet tested were not tested by default, except if a scientific rationale remained relevant.