Supplementary appendix This appendix formed part of the original submission and has been peer reviewed. We post it as supplied by the authors. This online publication has been corrected. The corrected version first appeared at thelancet.com/oncology on Dec 29, 2014. Supplement to: San-Miguel JF, Hungria VTM, Yoon S-S, et al. Panobinostat plus bortezomib and dexamethasone versus placebo plus bortezomib and dexamethasone in patients with relapsed or relapsed and refractory multiple myeloma: a multicentre, randomised, double-blind phase 3 trial. Lancet Oncol 2014; published online Sept 19. http://dx.doi.org/10.1016/S1470-2045(14)70440-1.
Transcript
Supplementary appendixThis appendix formed part of the original submission and has been peer reviewed. We post it as supplied by the authors.
This online publication has been corrected. The corrected version first appeared at thelancet.com/oncology on Dec 29, 2014.
Supplement to: San-Miguel JF, Hungria VTM, Yoon S-S, et al. Panobinostat plus bortezomib and dexamethasone versus placebo plus bortezomib and dexamethasone in patients with relapsed or relapsed and refractory multiple myeloma: a multicentre, randomised, double-blind phase 3 trial. Lancet Oncol 2014; published online Sept 19. http://dx.doi.org/10.1016/S1470-2045(14)70440-1.
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Supplementary Methods Statistical Analyses
Progression-free survival sensitivity analyses: Several sensitivity analyses were performed for the primary endpoint, progression-free survival (PFS). A stratified log-rank test, the derivation of the median with 95% CI, and calculation of hazard ratio from a Cox proportional hazards model, which included treatment arm and stratification factors, were repeated for each of the analyses as described.
Assess impact of missing response assessments (actual event) o Regardless of the number of preceding missing assessments, the actual event date of
progression, relapse, or death was used as the PFS event date Assess impact of missing response assessments (backdating event)
o In case of a documented PFS event after 1 or more subsequent missing response assessments, PFS was considered to have occurred at the next scheduled response assessment after the date of the last adequate response assessment
Assess impact of patients who are no longer followed for disease assessments (dropout); the following were considered PFS events:
o All patients who were censored in the primary analysis due to lack of or inadequately documented disease progression, relapse, or death while having progressive disease as the reason for end of treatment or study evaluation completion
o All patients who stopped disease follow-up due to new anticancer therapy; this applied for the following situations:
New anticancer therapy started (documented as on antineoplastic therapy after treatment discontinuation, per the case report form field); the start date of new anticancer therapy was considered the PFS event date
Reason for end of treatment or study evaluation completion is the start of a new antineoplastic therapy; the date of documentation was considered the PFS event date
o All patients whose PFS censoring reason was PFS event after ≥2 missing adequate assessments; the date of the disease progression, relapse, or death assessment was used as the PFS event date. In cases where more than 1 criterion applied, the earliest date was used as the PFS event date
Assess impact of using independent review committee (IRC) assessment o Used the IRC assessment instead of investigator’s evaluation for all patients. Used the IRC
assessment for patients with at least 1 M-protein assessment not performed by electrophoresis and used the investigator’s evaluation for patients with M-protein measurements
Investigator assessment as per-protocol set analysis o Included only the per-protocol set in the analysis
IRC assessment as per-protocol set analysis o Included only the per-protocol set in the analysis
Assess impact of prognostic factors o Used multivariate Cox regression model
Supportive analyses for PFS: A multivariate Cox model analysis was performed if the primary analysis of
PFS was statistically significant. The following prognostic factors in the Cox proportional hazards model were included:
Sex Age: <65 years, ≥65 years Race: Caucasian, Asian, other Renal impairment: yes, no Prior stem cell transplantation: yes, no Clinical staging of multiple myeloma according to ISS: stage I, stage II and III Geographic region: Europe, South East Asia, Western Pacific, Africa, Americas, Eastern
Mediterranean Prior use of bortezomib: yes, no Number of prior line of therapy: 1, 2/3
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Prior use of immunomodulatory agents (IMiDs; defined as thalidomide or lenalidomide): yes, no Prior use of IMiDs and bortezomib: yes, no Multiple myeloma characteristics: relapsed, relapsed-and-refractory
Several subgroup analyses were conducted for the same variables mentioned above in addition to the
cytogenetic risk group. Hazard ratios and 2-sided 95% CIs were provided based on the Cox proportional hazards model. To derive estimates by subgroup, this model included treatment and stratification factors.
Key secondary endpoint: Overall survival (OS), the key secondary endpoint, was tested only if the primary endpoint was statistically significant. In order to calculate the final OS analysis, the median OS of and PAN-BTZ- Dex was 20 months and Pbo-BTZ-Dex was 14·6 months and 20 months, respectively (HR = 0·73).Irrespective of whether OS was tested, alpha for OS was spent according to the OS group sequential plan at each PFS analysis. The final analysis of OS is planned when 415 survival events have occurred.
Other secondary endpoints: Other secondary endpoints of objective response rate (ORR), near complete or complete response (nCR/CR) rate, time to response, and response duration were calculated based on modified European Group for Blood and Marrow Transplantation criteria using the full analysis set. Point estimate and exact 95% 2-sided CI of ORR and nCR/CR rate were calculated and analyzed using unadjusted Cochran-Mantel-Haenszel test based on strata at randomization. The statistical test of nCR/CR rate was performed using post hoc analysis. Median time to response, time to progression, and response duration were estimated using the Kaplan-Meier method.
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Appendix Table 1: PANORAMA 1 Trial Investigators
Country
Institution
Principal Investigator
Number of Patients Randomized*
Korea
Seoul National University Hospital, Seoul Yoon, Sung-Soo 20
Brazil
Santa Casa de Misericordia de São Paulo Hospital, São Paulo Hungria, Vania 17
Greece
University of Athens, General Hospital of Athens, Alexandra Dimopoulos, Meletios Athanasios 16
Turkey
Ankara University Medicine, Ankara Beksac, Meral 16
Egypt
Alexandria University New Hospital, Alexandria Elghadour, Ashraf 14
Poland
Centrum Medyczne Warszawskiego, Warszawa Jedrzejczak, Wieslaw 13
Germany
Universitätsklinikum Kiel, Kiel Guenther, Andreas 12
Thailand Chulalongkorn University and King Chulalongkorn Memorial Hospital, Bangkok Na Nakorn, Thanyaphong 12
Kaiser Permanente – California Southern, Baldwin Park, CA Liang, John 1
United States
Cancer Center of the High Plains, Amarillo, TX Lim, Seah 1
United States
Swedish Cancer Institute, Seattle, WA Milder, Michael 1
United States
LSU Health Sciences Center, Shreveport, LA Mills, Glenn 1
United States
Missouri Cancer Associates, Columbia, MO Muscato, Joseph 1
United States
Columbia Basin Hematology, Kennewick, WA Rado, Thomas 1
United States
Western Pennsylvania Cancer Institute, Pittsburgh, PA Sahovic, Entezam 1
United States
East Orange VA Medical Center, East Orange, NJ Srinivas, Shanthi 1
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Country
Institution
Principal Investigator
Number of Patients Randomized*
United States
Dayton CCOP, Dayton, OH Yanes, Burhan 1 *The number randomizations totals 769 due to one patient being erroneously randomized twice. This was accounted for in the statistical analyses such that the total number of patients in the Full Analysis Set is 768.
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Appendix Table 2. Dose reduction steps for PANORAMA1
Starting Dose First Dose Reduction Second Dose Reduction Third Dose ReductionPAN/Pbo PAN/Pbo 20 mg PAN/Pbo 15 mg PAN/Pbo 10 mg Discontinue PAN/Pbo BTZ BTZ 1·3 mg/m2
ANC < 0.75 - 0.5 x 109/L Single occurrence within cycle, no change in dosing. Two or more occurrences within cycle, hold until return to ≥ Grade 2 ANC ≥ 1.0 x 10/L), and restart at same dose
Grade 4 (ANC < 0.5 x 109/L) Temporarily discontinue dosing until resolved to ≤ Grade 2 or baseline, then, restart at reduced dose level as per Appendix Table 2
Temporarily discontinue dosing and use supportive measures until resolved to ≤ Grade 2, or baseline, then, restart at reduced dose level as per Appendix Table 2.
NON-HEMATOLOGICAL TOXICITIES
GASTROINTESTINAL
Diarrhea** Grade 2 (4-6 stools/day over baseline, etc) persisting despite the use of optimal antidiarrheal medications
Temporarily discontinue dosing until resolved to ≤ Grade 1, or baseline, then restart at unchanged dose level
Grade 3 (≥ 7 stools/day over baseline, etc) despite the use of optimal antidiarrheal medications
Temporarily discontinue dosing until resolved to ≤ Grade 1, or baseline, then restart reduced by one dose level
Grade 4 (life-threatening consequences, hemodynamic collapse, etc) despite the use of optimal antidiarrheal medications
Discontinue dosing
Vomiting**/Nausea Grade 1and 2 not requiring treatment or controlled using standard anti-emetics
Maintain dose level
Grade 3 or 4 vomiting or Grade 3 nausea that cannot be controlled despite the use of standard anti-emetics
Temporarily discontinue dosing until resolved to ≤ grade 1, or baseline, then restart reduced by one dose level
Fatigue
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Fatigue Grade 3 Temporarily discontinue dosing until resolved to ≤ Grade 2, or baseline, then: - If resolved within 7 days after suspending dosing, then restart at an unchanged dose level - If resolved in more than 7 days after suspending dosing, then restart dosing reduced by one dose level
Grade 4 Temporarily discontinue dosing until resolved to ≤ Grade 2, or baseline, then restart dosing reduced by one dose level
HEPATIC
Total Bilirubin Grade 3 or 4 Temporarily discontinue dosing until resolved to ≤ Grade 2, or baseline, then restart dosing reduced by one dose level
Note: If Grade 3 or Grade 4 hyperbilirubinemia is due to the indirect component only, and hemolysis as the etiology has been ruled out as per institutional guidelines (e.g., review of peripheral blood smear and haptoglobin determination), then reduction of one dose level and continuation of treatment is at the discretion of the Investigator.
AST/SGOT, ALT/SGPT > 5-10 × ULN Temporarily discontinue dosing until resolved to ≤ grade 1 (or ≤ grade 2 if liver infiltration with tumor is present), or baseline, then: - If resolved within 7 days restart at unchanged dose level - If resolved in more than 7 days, then reduce dosing by one dose level
> 10 × ULN Temporarily discontinue dosing until resolved to ≤ grade 1, or baseline, then restart dosing reduced by one dose level
All dose modifications should be based on the worst preceding toxicity. * Common Terminology Criteria for Adverse Events (CTCAE Version 3.0) ** It is critical that electrolyte abnormalities be followed closely and corrected prior to dosing
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Appendix Table 4. Criteria for dosing delays, dose-reductions, and re-initiation of PAN/placebo due to study drug-related QTcF abnormalities (cycle 1, cycles 2-8)
ECGs to be performed at specified time point
Abnormality Noted Dose Modification Guideline - At any time during a cycle of therapy (including intended day of dosing)
Dose modifications are based on local readings of the average QTcF of triplicate ECGs.
Cycle 1 dose modification criteria:
Pre-dose on cycle 1, days 1 and 5:
3 ECGs separated by 5- 10 minutes, obtained prior to PAN/placebo dosing
Day 1: Average QTcF > 450 msec
Day 5: Average QTcF: ≥ 480 msec to < 500 msec OR > 60 msec increase from baseline average
Check and correct the patient’s serum potassium, magnesium, calcium and phosphorus immediately, as well as evaluate con-meds.
Notify Sponsor and transmit to eRT immediately for prompt review.
If abnormality noted on Day 1 of Cycle 1: Repeat 3 pre-dose ECGs. If the 3 pre-dose ECGs: Do not meet criteria again, discontinue patient from study. Do meet criteria for dosing; administer study drug treatment.
If abnormality noted on Day 5 of Cycle 1: Delay dose at least 3 days and repeat 3 pre-dose ECGs. If the repeat 3 pre-dose ECGs: Do not meet pre-dose ECG criteria again, discontinue patient from study. Do meet pre-dose ECG criteria for dosing and QT prolongation determined to be related to study drug, resume study drug treatment with a dose reduction of 5 mg. If however, it was determined that the QT prolongation was secondary to electrolyte abnormalities or con-meds, continue at the same dose level. Repeat ECGs - pre-dose (× 3), 3-hours post-dose (× 3), on the next scheduled dosing day.
ECGs to be performed at specified time point
Abnormality Noted Dose Modification Guideline - At any time during a cycle of therapy (including intended day of dosing)
Dose modifications are based on local readings of the average QTcF of triplicate ECGs.
Average QTcF ≥ 500 msec Check and correct the patient’s serum potassium, magnesium, calcium and phosphorus immediately. Notify Sponsor and transmit to eRT immediately for prompt review.
Discontinue patient from study therapy If however, it was determined that the QT prolongation was secondary to electrolyte abnormalities or con- meds: Omit dose. On the next scheduled dosing day continue at the same dose level. Repeat ECGs - pre-dose (× 3), 3-hours post-dose (× 3), on the next scheduled dosing day.
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Post-dose on cycle 1, days 1 and 5:
3 ECGs separated by 5- 10 minutes, obtained 3 hours +/- 0.5 hours after PAN/placebo dosing:
Average QTcF ≥ 480 msec to < 500 msec
OR
> 60 msec increase from baseline
Check and correct the patient’s serum potassium, magnesium, calcium and phosphorus immediately, as well as evaluate con-meds.
Monitor ECG hourly or by telemetry until at least 2 consecutive hourly ECGs performed at least 6 hours post dose are <480.
Notify Sponsor and transmit to eRT immediately for prompt review.
Next scheduled dosing day: repeat 3 pre-dose ECGs. If these 3 pre-
dose ECGs: Do not meet pre-dose ECG criteria for dosing (average QTcF ≤ 480 msec), discontinue patient from study.
Do meet pre-dose ECG criteria for dosing (average QTcF ≤ 480 msec) and QT prolongation determined to be related to study drug, resume study drug treatment with a dose reduction of 5 mg. If however, it was determined that the QT prolongation was secondary to electrolyte abnormalities or con-meds, continue at the same dose level. Repeat ECGs - pre-dose (x3), 3- hours post-dose (x3) on the next scheduled dosing day.
Average QTcF ≥ 500 msec Check and correct the patient’s serum potassium, magnesium, calcium and phosphorus immediately.
Notify Sponsor and transmit to eRT immediately for prompt review.
Discontinue patient from study therapy If however, it was determined that the QT prolongation was secondary to electrolyte abnormalities or con- meds: omit dose. On the next scheduled dosing day continue at the same dose level. Repeat ECGs - pre- dose (× 3), 3-hours post-dose (× 3), on the next scheduled dosing day.
Cycles 2-8 dose modification criteria:
Pre-dose on day 1 of each cycle
3 ECGs separated by 5- 10 minutes, obtained prior to PAN/placebo dosing
Day 1:
Average QTcF > 450 msec
Check and correct the patient’s serum potassium, magnesium, calcium and phosphorus immediately, as well as evaluate con-meds.
Notify Sponsor and transmit to eRT immediately for prompt review.
If abnormality noted on Day 1 of Cycles 2-8: Repeat 3
pre-dose ECGs. If the 3 pre-dose ECGs: Do not meet criteria again, discontinue patient from study. Do meet criteria for dosing; administer study drug treatment.
Average QTcF ≥ 500 msec Check and correct the patient’s serum potassium, magnesium, calcium and phosphorus immediately.
Notify Sponsor and transmit to eRT immediately for prompt review.
Discontinue patient from study therapy.
If however, it was determined that the QT prolongation was secondary to electrolyte abnormalities or con- meds: Omit dose. On the next scheduled dosing day continue at the same dose level. Repeat ECGs - pre-dose (x3), 3-hours post-dose (x3), on the next scheduled dosing day.
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Post-dose on day 1 of each cycle:
3 ECGs separated by 5- 10 minutes, obtained 3 hours +/- 0.5 hours after PAN dosing:
Average QTcF ≥ 480 msec to < 500 msec
OR
> 60 msec increase from baseline
Check and correct the patient’s serum potassium, magnesium, calcium and phosphorus immediately, as well as evaluate con-meds.
Monitor ECG hourly or by telemetry until at least 2 consecutive hourly ECGs performed at least 6 hours post dose are <480.
Notify Sponsor and transmit to eRT immediately for prompt review.
Next scheduled dosing day: repeat 3 pre-dose ECGs. If these 3 pre- dose ECGs: Do not meet pre-dose ECG criteria for dosing (average QTcF ≤ 480 msec), discontinue patient from study.
Do meet pre-dose ECG criteria for dosing (average QTcF ≤ 480 msec) and QT prolongation determined to be related to study drug, resume study drug treatment with a dose reduction of 5 mg. If however, it was determined that the QT prolongation was secondary to electrolyte abnormalities or con-meds, continue at the same dose level. Repeat ECGs - pre-dose (× 3), 3- hours post-dose (× 3) on the next scheduled dosing day.
Average QTcF ≥ 500 msec Check and correct the patient’s serum potassium, magnesium, calcium and phosphorus immediately.
Notify Sponsor and transmit to eRT immediately for prompt review.
Discontinue patient from study therapy If however, it was determined that the QT prolongation was secondary to electrolyte abnormalities or con- meds: omit dose. On the next scheduled dosing day continue at the same dose level. Repeat ECGs - pre- dose (×3), 3-hours post-dose (× 3), on the next scheduled dosing day.
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Appendix Table 5. Drug related adverse events dose modification guidelines for bortezomib
CTCAE Category Dose Modification Guideline - At any time during a cycle of therapy (including intended day of dosing)
Severity of Peripheral Neuropathy Signs and Symptoms
Modification of Dose and Regimen
Grade 1 (paresthesias and/or loss of reflexes) without pain or loss of function
No action
Grade 1 with pain or Grade 2 (interfering with function but not with activities of daily living)
Reduce by one dose level
Grade 2 with pain or Grade 3 (interfering with activities of daily living)
Hold BTZ therapy until toxicity resolves to < Grade 2
When toxicity resolves, reinitiate with a reduction by one dose levels and change treatment schedule to once per week. (day 1 and 8) during cycles 1-8 During TP2 cycles discontinue BTZ
Grade 4 (Permanent sensory loss that interferes with function) Discontinue BTZ
Grading based on NCI Common Terminology Criteria CTCAE v3.0
Gastrointestinal Dyspepsia, gastric or duodenal ulcer, gastritis Grade 1-2 (requiring medical management)
Treat with H2 blockers, sucralfate, or omeprazole. If symptoms persist despite above measures, decrease Dex dose by 1 dose level
> Grade 3 (requiring hospitalization or surgery)
Hold Dex until symptoms adequately controlled. Restart and decrease one dose level of current dose along with concurrent therapy with H2 blockers, sucralfate, or omeprazole. If symptoms persist despite above measures, discontinue Dex and do not resume
Acute pancreatitis Discontinue Dex and do not resume
Cardiovascular Edema > Grade 3 (limiting function and unresponsive to therapy or nasarca)
Diuretics as needed, and decrease Dex dose by 1 dose level; if edema persists despite above measures, decrease dose another dose level. Discontinue Dex and do not resume if symptoms persist despite second reduction
Neurology Confusion or Mood alteration > Grade 2 (interfering with function +/- interfering with activities of daily living)
Hold Dex until symptoms resolve. Restart with one dose level reduction. If symptoms persist despite above measures, discontinue Dex. Do not resume.
Musculoskeletal Muscle weakness > Grade 2 (symptomatic and interfering with function +/- interfering with activities of daily living)
Decrease Dex dose by one dose level. If weakness persists despite above measures decrease dose by one dose level. Discontinue Dex and do not resume if symptoms persist
Metabolic Hyperglycemia > Grade 3 or higher
Treatment with insulin or oral hypoglycemics as needed. If uncontrolled despite above measures, decrease dose by one dose level until levels are satisfactory
*Analysis included the event whenever it occurred, even after ≥2 missing adequate assessments. †Analysis used the date of the next scheduled assessment for events occurring after ≥1 missing adequate assessments. ‡ Analysis included subsequent antineoplastic therapy, reason for end of treatment as disease progression without investigator documentation, and disease progression after ≥2 missing adequate assessments as events. §IRC assessment was used for all patients. ¶IRC assessment was used for patients without M-protein measurements by electrophoresis. For all other patients, investigator assessment was used. ||Baseline covariates included in the Cox proportional hazard model are treatment group; age group; renal impairment; prior stem cell transplantation; clinical staging according to ISS, sex, race, and geographic region; prior use of IMiDs; prior use of bortezomib and IMiDs; prior use of bortezomib (yes vs no); and number of prior lines of therapy (1 vs 2/3) Hazard ratio and 95% CI of PAN-BTZ-Dex versus Pbo-BTZ-Dex are obtained from stratified Cox model. The 2-sided p value is obtained from the stratified log- rank test. p values for other than the primary analysis are presented for descriptive purposes and for an assessment of the consistency and robustness of the primary analysis in terms of statistical significance. BTZ, bortezomib; Dex, dexamethasone; IMiDs, immunomodulatory drugs; PAN, panobinostat; Pbo, placebo.
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Appendix Table 9. Progression-Free Survival by Stratification Factors
Treatment Group Median Progression-Free Survival (95% CI), mo [n]
Hazard Ratio (95% CI) PAN-BTZ-Dex Pbo-BTZ-Dex1 prior line of therapy 12·3 (9·5–14·6)
[n=178] 8·5 (7·7–10·4)
[n=174] 0·66 (0·50–0·86)
2–3 prior lines of therapy 12 (9·5–13·7) [n=209]
7·6 (6·0–8·7) [n=207]
0·64 (0·50–0·83)
Prior treatment with bortezomib 11 (8·3–13·7) [n=169]
7·6 (5·9–7·9) [n=167]
0·58 (0·44–0·77)
No prior treatment with bortezomib 12·5 (10·2–14·2) [n=218]
Appendix Figure 1. Kaplan-Meier Plot of Time to Progression by Treatment Group per Investigator’s Assessment of the Full Analysis Set
Appendix Figure 1. A median of 12·71 (95% CI, 11.30–14.06) months was observed for the panobinostat (PAN) plus bortezomib (BTZ) and dexamethasone (Dex) arm and a median of 8·54 (95% CI, 11.30–14.06) months for the placebo (Pbo) plus BTZ and Dex arm (hazard ratio, 0·58 [95% CI, 0·48, 0·71]; p<0·0001).
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Appendix Figure 2. Frequency and grade of diarrhea by dose from a phase 1 study of panobinostat in combination with bortezomib
Appendix Figure 2. Patients were enrolled and treated with panobinostat and bortezomib in successive cohorts in a phase 1b study as previously described (San Miguel et al. J Clin Oncol 2013; 31: 3696–3703). An analysis of the incidence of diarrhea demonstrated that grade 3/4 diarrhea occurred in patients treated in cohorts in which bortezomib was administered twice weekly at doses of 1.3 mg/m2. BTZ=bortezomib. PAN=panobinostat.
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