A Study Evaluating Venetoclax (ABT-199) in Multiple Myeloma Subjects Who Are Receiving Bortezomib and Dexamethasone as Standard Therapy

Relapsed/Refractory Multiple Myeloma Clinical Trial

— Bellini  

Official title:

A Phase 3, Multicenter, Randomized, Double Blind Study of Bortezomib and Dexamethasone in Combination With Either Venetoclax or Placebo in Subjects With Relapsed or Refractory Multiple Myeloma Who Are Sensitive or Naïve to Proteasome Inhibitors

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02755597
• Other study ID #: M14-031
• Secondary ID: 2015-004411-20
• Status: Completed
• Phase: Phase 3
• Start date: July 11, 2016
• Est. completion date: August 15, 2022

Study information

• Verified date: August 2023
• Source: AbbVie
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This was a Phase 3, multicenter, randomized, double blind, placebo-controlled study evaluating the efficacy and safety of venetoclax plus bortezomib and dexamethasone in participants with relapsed or refractory multiple myeloma who are considered sensitive or naïve to proteasome inhibitors and received 1 to 3 prior lines of therapy for multiple myeloma.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 291
• Est. completion date: August 15, 2022
• Est. primary completion date: March 15, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 99 Years

Eligibility

Inclusion Criteria:

• Eastern Cooperative Oncology Group (ECOG) performance score = 2

• Participant has documented relapsed or progressive multiple myeloma on or after any regimen or who are refractory to the most recent line of therapy. Relapsed myeloma is defined as previously treated myeloma that progresses and requires initiation of salvage therapy, but does not meet the criteria for refractory myeloma. Refractory myeloma is defined as disease that is nonresponsive (failure to achieve minimal response or development of progressive disease [PD]) while on primary or salvage therapy, or progresses within 60 days of last therapy.

• Participant must have received prior treatment with at least one, but no more than three, prior lines of therapy for multiple myeloma. A line of therapy consists of = 1 complete cycle of a single agent, a regimen consisting of combination of several drugs, or a planned sequential therapy of various regimens.

• Prior treatment with bortezomib or other proteasome inhibitor is allowed, provided ALL of the following criteria are met: Disease is NOT refractory to any proteasome inhibitor, defined as no disease progression (i.e., PD, per International Myeloma Working Group [IMWG] or European Society for Blood and Marrow Transplantation [EBMT] criteria) while receiving proteasome inhibitor therapy or within 60 days after the last dose, AND best response achieved with any proteasome inhibitor therapy (alone or in combination) was at least a Partial Response (PR), AND participant did not discontinue any proteasome inhibitor due to intolerance or = Grade 3 related toxicity.

• Participant has measurable disease at Screening, defined as at least one of the following: Serum M-protein = 0.5 g/dL, OR Urine M-protein = 200 mg in 24-hours, OR serum immunoglobulin free light chain (FLC) = 10 mg/dL provided serum FLC ratio is abnormal.

Exclusion Criteria:

• Participant is refractory to any proteasome inhibitor, defined as progression on or within 60 days of the last dose of a proteasome inhibitor-containing regimen.

• Participant has had prior treatment with proteasome inhibitor within 60 days prior to first dose of study drug.

• Participant has any of the following conditions:

Non-secretory multiple myeloma, active plasma cell leukemia i.e., either 20% of peripheral white blood cells or greater than 2.0 X 10^9/liter (L) circulating plasma cells by standard differential, Waldenstrom's macroglobulinemia, amyloidosis, POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes), known Human Immunodeficiency Viral (HIV) infection, active hepatitis B or C infection based on blood screen tests, significant cardiovascular disease, including uncontrolled angina, severe or uncontrolled arrhythmia, recent myocardial infarction within 6 months of randomization, or congestive heart failure New York Heart Association (NYHA) Class = 3, major surgery within 4 weeks prior to randomization, acute infections requiring parenteral therapy (antibiotic, antifungal, or antiviral) within 14 days prior to randomization, peripheral neuropathy = Grade 3 or = Grade 2 with pain within 2 weeks prior to randomization, uncontrolled diabetes or uncontrolled hypertension within 14 days prior to randomization, any other medical condition that, in the opinion of the Investigator, would adversely affect the participant's participation in the study

• Participant has a history of other active malignancies, including myelodysplastic syndrome (MDS), within the past 3 years prior to study entry, with the following exceptions: Adequately treated in situ carcinoma of the cervix uteri or the breast, basal cell carcinoma of the skin or localized squamous cell carcinoma of the skin, prostate cancer Gleason grade 6 or lower AND with stable Prostate Specific Antigen (PSA) levels off treatment, previous malignancy with no evidence of disease confined and surgically resected (or treated with other modalities) with curative intent and unlikely to impact survival during the duration of the study

• If participant had prior allogeneic stem cell transplant (SCT), participant has evidence of ongoing graft-versus-host disease (GvHD)

Related Conditions & MeSH terms

• Multiple Myeloma
• Neoplasms, Plasma Cell
• Relapsed/Refractory Multiple Myeloma

Intervention

Drug:
• Venetoclax
Participants self-administered venetoclax tablets by mouth QD in combination with bortezomib. Venetoclax was to be given before other agents administered on the same day, if applicable. Each venetoclax dose was to be taken all at one time with approximately 240 mL of water within 30 minutes after completion of breakfast or the subject's first meal of the day. Tablets were to be swallowed whole and must not have been broken, chewed, or crushed. On days that pre-dose PK sampling was required, dosing occurred at the clinic to facilitate PK sampling.
• Bortezomib
Bortezomib (subcutaneous injection [preferred] or IV) was given following administration of venetoclax or placebo in Cycles 1 -8 on Days 1, 4, 8 and 11, and for Cycles 9 and beyond, on Days 1, 8, 15 and 22 and was to be administered per the prescribing information. The route of administration was to stay the same during the study.
• Dexamethasone
Dexamethasone was to be given orally, administered per the prescribing information, the day of bortezomib dosing and the following day, given the protocol-defined dosing window (bortezomib dosing window is ± 1 day) is maintained. If bortezomib was interrupted or a dose is skipped, dexamethasone was to be administered as scheduled per protocol (unless dexamethasone was interrupted due to toxicity).
• Placebo for venetoclax
Participants self-administered placebo tablets by mouth QD in combination with bortezomib. Placebo was to be given before other agents administered on the same day, if applicable. Each placebo dose was to be taken all at one time with approximately 240 mL of water within 30 minutes after completion of breakfast or the subject's first meal of the day. Tablets were to be swallowed whole and must not have been broken, chewed, or crushed. On days that pre-dose PK sampling was required, dosing occurred at the clinic to facilitate PK sampling.

Locations

Country	Name	City	State
Australia	Box Hill Hospital /ID# 149112	Box Hill	Victoria
Australia	Royal Prince Alfred Hospital /ID# 149108	Camperdown	New South Wales
Australia	Concord Repatriation General Hospital /ID# 149106	Concord	New South Wales
Australia	Royal Brisbane and Women's Hospital /ID# 149105	Herston	Queensland
Australia	Royal Hobart Hospital /ID# 149111	Hobart	Tasmania
Australia	Liverpool Hospital /ID# 149110	Liverpool	New South Wales
Australia	Alfred Health /ID# 150085	Melbourne	Victoria
Australia	Peter MacCallum Cancer Ctr /ID# 149107	Melbourne	Victoria
Australia	Fiona Stanley Hospital /ID# 148967	Murdoch	Western Australia
Australia	Perth Blood Institute Ltd /ID# 148966	Nedlands	Western Australia
Australia	The Queen Elizabeth Hospital /ID# 149104	Woodville South	South Australia
Brazil	Hospital das Clinicas da Universidade Federal de Goiás /ID# 149290	Goiania	Goias
Brazil	Liga Norte Riograndense Contra o Câncer /ID# 149023	Natal	Rio Grande Do Norte
Brazil	Hospital Sao Lucas da PUCRS /ID# 149027	Porto Alegre	Rio Grande Do Sul
Brazil	Instituto Nacional de Câncer José Alencar Gomes da Silva (INCA) /ID# 149020	Rio de Janeiro
Brazil	Hospital das Clinicas da Faculdade de Medicina da Universidade de Sao Paulo /ID# 149025	Sao Paulo
Brazil	Clinica Sao Germano /ID# 149851	São Paulo	Sao Paulo
Canada	CISSS de la Monteregie /ID# 149844	Greenfield Park	Quebec
Canada	Victoria Hospital /ID# 149846	London	Ontario
France	CHRU de Brest - Hopital Morvan /ID# 149299	Brest
France	CHU Grenoble - Hopital Michallon /ID# 149301	La Tronche
France	CHU Limoges - Dupuytren 1 /ID# 149292	Limoges CEDEX 1	Franche-Comte
France	CHU de Nantes, Hotel Dieu -HME /ID# 149294	Nantes	Pays-de-la-Loire
France	Duplicate_Centre Hospitalier Lyon Sud /ID# 149300	Pierre Benite CEDEX	Rhone
Germany	Charite Universitaetsmedizin Berlin - Campus Mitte /ID# 148949	Berlin
Germany	Universitaetsklinikum Carl Gustav Carus an der TU Dresden /ID# 148948	Dresden
Germany	Asklepios Klinik Altona /ID# 150116	Hamburg
Hungary	Del-pesti Centrumkorhaz Orszagos Hematologiai es Infektologiai Intezet /ID# 152518	Budapest
Hungary	Semmelweis Egyetem /ID# 152519	Budapest
Hungary	Semmelweis Egyetem /ID# 152520	Budapest
Hungary	Debreceni Egyetem Klinikai Kozpont /ID# 152517	Debrecen	Hajdu-Bihar
Hungary	Somogy Megyei Kaposi Mor Oktato Korhaz /ID# 152516	Kaposvár	Somogy
Ireland	University Hospital Galway /ID# 149061	Galway
Italy	Azienda Ospedaliero Universitaria Ospedali Riuniti di Ancona /ID# 148942	Ancona
Italy	IRCCS Azienda Ospedaliero-Universitaria di Bologna /ID# 148936	Bologna
Italy	Azienda Ospedaliero-Universitaria Policlinico Umberto I /ID# 148939	Rome	Lazio
Italy	Ospedale S.Eugenio /ID# 148938	Rome
Italy	A.O.U. Città della Salute e della Scienza di Torino/Ospedale Molinette /ID# 148943	Turin
Japan	National Cancer Center Hospital /ID# 151039	Chuo-ku	Tokyo
Japan	Kyushu University Hospital /ID# 150896	Fukuoka-shi	Fukuoka
Japan	National Hospital Organization Mito Medical Center /ID# 151051	Higashi Ibaraki-gun	Ibaraki
Japan	Hiroshima Red Cross Hospital & Atomic-bomb Survivors Hospital /ID# 150242	Hiroshima-shi	Hiroshima
Japan	Saitama Medical Center /ID# 151044	Kawagoe-shi	Saitama
Japan	Kobe City Medical Center General Hospital /ID# 150944	Kobe-shi	Hyogo
Japan	The Cancer Institute Hospital Of JFCR /ID# 150780	Koto-ku	Tokyo
Japan	Duplicate_Kyoto Prefectural University of Medicine /ID# 150719	Kyoto-shi	Kyoto
Japan	JCHO Kyoto Kuramaguchi Medical /ID# 150781	Kyoto-shi	Kyoto
Japan	Gunma University Hospital /ID# 150275	Maebashi-shi	Gunma
Japan	Nagoya City University Hospital /ID# 150943	Nagoya shi	Aichi
Japan	Ogaki Municipal Hospital /ID# 150783	Ogaki-shi	Gifu
Japan	Okayama Medical Center /ID# 150717	Okayama-shi	Okayama
Japan	Japanese Red Cross Osaka Hospital /ID# 150716	Osaka-shi	Osaka
Japan	Tohoku University Hospital /ID# 150945	Sendai-shi	Miyagi
Japan	National Hospital Organization Shibukawa Medical Center /ID# 150281	Shibukawa-shi	Gunma
Japan	Japanese Red Cross Medical Center /ID# 149902	Shibuya-ku	Tokyo
Japan	National Hospital Organization Disaster Medical Center /ID# 150784	Tachikawa-shi	Tokyo
Japan	Tochigi Cancer Center /ID# 150192	Utsunomiya-shi	Tochigi
Korea, Republic of	National Cancer Center /ID# 150889	Goyang	Gyeonggido
Korea, Republic of	Chonnam National University Hospital /ID# 150894	Gwangju
Korea, Republic of	Gachon University Gil Medical Center /ID# 150893	Incheon
Korea, Republic of	Seoul National University Bundang Hospital /ID# 150888	Seongnam	Gyeonggido
Korea, Republic of	Duplicate_Yonsei University Health System, Severance hospital. /ID# 150891	Seoul	Seoul Teugbyeolsi
Korea, Republic of	Samsung Medical Center /ID# 150892	Seoul
Korea, Republic of	Seoul National University Hospital /ID# 150890	Seoul
Korea, Republic of	The Catholic University of Korea, Seoul St. Mary's Hospital /ID# 150895	Seoul
Russian Federation	Kuzbass Regional Clinical Hospital /ID# 148955	Kemerovo	Kemerovskaya Oblast
Russian Federation	Central Clinical Hospital RZHD Medicine /ID# 148954	Moscow
Russian Federation	Clinical Oncology Dispensary of Omsk /ID# 148953	Omsk
Russian Federation	LLC Novaya Klinika /ID# 148974	Pyatigorsk	Stavropol Skiy Kray
Russian Federation	State Institution of Health of the Ryazan Regional Clinical Hospital /ID# 148956	Ryazan	Ryazanskaya Oblast
Russian Federation	Samara State Medical University /ID# 148952	Samara
Russian Federation	Bashkir State Medical University /ID# 151206	Ufa
Spain	Hospital Duran i Reynals /ID# 148989	Hospitalet de Llobregat	Barcelona
Spain	Hospital Universitario 12 de Octubre /ID# 148981	Madrid
Spain	Hospital Universitario de la Princesa /ID# 148980	Madrid
Spain	Hospital Universitario Dr. Peset /ID# 148986	Valencia
Taiwan	Changhua Christian Hospital /ID# 154447	Changhua City, Changhua County
Taiwan	China Medical University Hospital /ID# 154446	Taichung City
Taiwan	National Taiwan University Hospital /ID# 154444	Taipei City
Taiwan	Taipei Veterans General Hosp /ID# 154445	Taipei City
Ukraine	Communal Nonprofit Enterprise Cherkasy Regional Oncology Dispensary /ID# 152414	Cherkasy
Ukraine	Municipal Non-Profit Enterprise City Clinical Hospital 4 of Dnipro City Council /ID# 152411	Dnipro
Ukraine	National Cancer Institute /ID# 152413	Kyiv
United Kingdom	Blackpool Teaching Hospitals NHS Foundation Trust /ID# 149058	Blackpool
United Kingdom	East Kent Hospitals University NHS Foundation Trust /ID# 149059	Canterbury
United Kingdom	Leicester Royal Infirmary /ID# 149057	Leicester	England
United Kingdom	Barts Health NHS Trust /ID# 149050	London	London, City Of
United Kingdom	King's College Hospital NHS Foundation Trust /ID# 149045	London
United Kingdom	University College London Hospitals NHS Foundation Trust /ID# 149044	London
United Kingdom	Manchester University NHS Foundation Trust /ID# 149046	Manchester
United Kingdom	Nottingham University Hospitals NHS Trust /ID# 149047	Nottingham	Nottinghamshire
United Kingdom	Barking, Havering and Redbridge University Hospitals NHS Trust /ID# 149055	Romford
United Kingdom	The Royal Wolverhampton NHS Trust /ID# 149043	Wolverhampton
United States	Rocky Mountain Regional VA Medical Center/Eastern Colorado Health Care System /ID# 156524	Aurora	Colorado
United States	Univ of Colorado Cancer Center /ID# 149130	Aurora	Colorado
United States	Gabrail Cancer Center Research /ID# 149098	Canton	Ohio
United States	Duke Cancer Center /ID# 149099	Durham	North Carolina

Sponsors (2)

Lead Sponsor	Collaborator
AbbVie	Genentech, Inc.

Countries where clinical trial is conducted

United States,  Australia,  Brazil,  Canada,  France,  Germany,  Hungary,  Ireland,  Italy,  Japan,  Korea, Republic of,  Russian Federation,  Spain,  Taiwan,  Ukraine,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Progression-free Survival (PFS)	PFS is defined as the number of days from the date the participant was randomized to the date of the first documented progressive disease (PD) as determined by an Independent Review Committee (IRC) or death due to any cause, whichever occurs first. PFS was analyzed by Kaplan-Meier methodology.	Median duration of follow-up was 28.6 months for the venetoclax group and 28.6 months for the placebo group
Secondary	Very Good Partial Response (VGPR) or Better Response Rate	The percentage of participants with documented best overall response of Very Good Partial Response (VGPR) or better (VGPR, Complete response [CR], or Stringent complete response [sCR]) per 2016 standard International Myeloma Working Group (IMWG) criteria as determined by an Independent Review Committee (IRC) was computed.	Response was assessed at Cycle 1, Day 1, and on Day 1 of every cycle thereafter; median time on follow-up was 28.6 months for the venetoclax group and 28.6 months for the placebo group
Secondary	Progression-Free Survival (PFS) in Participants With High B-cell Lymphoma 2 (BCL-2) Expression	PFS is defined as the number of days from the date the participant was randomized to the date of the first documented progressive disease (PD) per investigator assessment or death due to any cause, whichever occurs first. PFS was analyzed by Kaplan-Meier methodology.; BCL-2 expression was determined through central laboratory testing by immunohistochemistry (IHC) and based on a pre-specified scoring algorithm. High clinical score of 2+: =50% of tumor cells with moderate or higher cytoplasmic staining but < 50% of tumor cells with strong staining intensity; high clinical score of 3+: =50% of tumor cells with strong cytoplasmic staining.	Median duration of follow-up was 28.6 months for the venetoclax group and 28.6 months for the placebo group
Secondary	Duration of Response (DOR)	DOR is defined as the number of days from the participant's date of first documented response (partial response [PR] or better) to the date of first documented progressive disease (PD) as determined by an Independent Review Committee (IRC) or death due to multiple myeloma, whichever occurs first. DOR was analyzed by Kaplan-Meier methodology.	Response was assessed at Cycle 1, Day 1, and on Day 1 of every cycle thereafter; median time on follow-up was 28.6 months for the venetoclax group and 28.6 months for the placebo group
Secondary	Mean Change From Baseline in Brief Pain Inventory - Short Form (BPI-SF) Worst Pain	The BPI-SF is a pain-specific measure developed to assess patient-reported severity (or intensity) of pain (4 items) and the impact of pain on daily functioning (7 items) in patients with cancer pain. The four pain severity items assess pain at its "worst in last 24 hours," "least in last 24 hours," "average," and "now" (current pain). For these items, participants are asked to rate their pain on an 11-point numeric rating scale with anchors of 0 (no pain) and 10 (pain as bad as you can imagine). The Worst Pain scores range from 0 to 10, with higher scores indicating severe pain. Negative changes from baseline indicate improvement.	Baseline; Cycle 3 (Cycles 1 - 8 are 21 days, Cycles 9 and beyond are 35 days) through Cycle 47, collected on Day 1 of every other cycle and at the Treatment Completion Visit (TCV) while participant is on treatment
Secondary	Mean Change From Baseline in Physical Functioning Scale of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30)	The QLQ-C30 is a 30-item subject self-report questionnaire composed of both multi-item and single scales, including five functional scales (physical, role, emotional, social, and cognitive), three symptom scales (fatigue, nausea and vomiting, and pain), a global health status/quality of life scale, and six single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). For the Physical Functioning scale, participants rate five items on a four-point scale, with 1 as "not at all" and 4 as "very much." The Physical Functioning Scale scores range from 0 to 100 and were calculated per the EORTC QLQ-C30 Scoring Manual (3rd edition), version 3.0. A high scale score represents high/healthy level of functioning. Positive changes from baseline indicate improvement.	Baseline; Cycle 3 (Cycles 1 - 8 are 21 days, Cycles 9 and beyond are 35 days) through Cycle 47, collected on Day 1 of every other cycle and at the Treatment Completion Visit (TCV) while participant is on treatment
Secondary	Mean Change From Baseline in Global Health Status/Quality of Life Scale of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30)	The QLQ-C30 is a 30-item subject self-report questionnaire composed of both multi-item and single scales, including five functional scales (physical, role, emotional, social, and cognitive), three symptom scales (fatigue, nausea and vomiting, and pain), a global health status/quality of life scale, and six single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). For the Global Health Status/Quality of Life scale, participants rate two items on a seven point scale, with 1 as "very poor" and 7 as "excellent." The Global Health Status/Quality of Life scale ranges from 0 to 100 and was calculated per the EORTC QLQ-C30 Scoring Manual (3rd edition), version 3.0. A high score for the global health status/QoL represents a high QoL. Positive changes from baseline indicate improvement.	Baseline; Cycle 3 (Cycles 1 - 8 are 21 days, Cycles 9 and beyond are 35 days) through Cycle 47, collected on Day 1 of every other cycle and at the Treatment Completion Visit (TCV) while participant is on treatment
Secondary	Mean Change From Baseline in Patient Reported Outcomes Measurement Information System [PROMIS] Cancer Fatigue Short Form [SF] Score	PROMIS Cancer Fatigue SF is a seven item questionnaire that assesses the impact and experience of fatigue over the past 7 days. All questions employ the following five response options: 1 = Not at all, 2 = A little bit, 3 = Somewhat, 4 = Quite a bit, and 5 = Very much. The total raw score is the sum of the responses to each question and is converted to a T-score. The T-score re-scales the total raw score to a standardized score with a mean of 50 and a standard deviation of 10. The [PROMIS] Cancer Fatigue Short Form [SF] 7a T-Scores range from 29.4 to 83.2, with higher scores indicating more fatigue. Negative changes from baseline indicate improvement.	Baseline; Cycle 3 (Cycles 1 - 8 are 21 days, Cycles 9 and beyond are 35 days) through Cycle 47, collected on Day 1 of every other cycle and at the Treatment Completion Visit (TCV) while participant is on treatment
Secondary	Overall Survival (OS).	OS is defined as the number of days from the date of randomization to the date of death due to any cause. All events of death were to be included, regardless of whether the event occurred while the participant was still taking study drug or after the participant discontinued study drug. If a participant is not known to have died, OS was censored at the date of last contact. The distribution of OS was estimated using Kaplan-Meier methodology.	Median duration of follow-up was 45.6 months for the venetoclax group and 45.6 months for the placebo group
Secondary	Time to Progression (TTP)	TTP is defined as the number of days from the date of randomization to the date of first documented progressive disease (PD) as determined by an Independent Review Committee (IRC) or death due to multiple myeloma, whichever occurs first. TTP was analyzed by Kaplan-Meier methodology.	Median time on follow-up up was 28.6 months for the venetoclax group and 28.6 months for the placebo group
Secondary	Overall Response Rate (ORR)	Overall response rate is defined as the percentage of participants with documented best overall response of Partial Response (PR) or better (PR, Very good partial response [VGPR], Complete response [CR], or Stringent complete response [sCR]) per International Myeloma Working Group (IMWG) criteria as determined by an Independent Review Committee (IRC).	Response was assessed at Cycle 1, Day 1, and on Day 1 of every cycle thereafter; median time on follow-up was 28.6 months for the venetoclax group and 28.6 months for the placebo group
Secondary	Minimal Residual Disease (MRD) Negativity Rate	MRD negativity rate is defined as the percentage of participants who have negative MRD by bone marrow aspirate at any time point after randomization and before progression or starting subsequent therapy. MRD negativity was defined at 10^-5 threshold (less than one residual myeloma cell per 10^5 total nucleated cells) as measured by centralized testing of bone marrow aspirate by Next Generation Sequencing (NGS). MRD positive participants include those of which all tested samples were found to be MRD positive or indeterminate. Participants with missing or unevaluable MRD status were considered as MRD positive.	Assessed at Screening; to confirm a stringent Complete Response (sCR) or Complete Response (CR); at 6 months and 12 months post-confirmed CR/sCR