A Study of Atezolizumab With or Without Tiragolumab in Participants With Unresectable Esophageal Squamous Cell Carcinoma Whose Cancers Have Not Progressed Following Definitive Concurrent Chemoradiotherapy

Esophageal Squamous Cell Carcinoma Clinical Trial

— SKYSCRAPER-07  

Official title:

A Phase III, Randomized, Double-Blind, Placebo-Controlled Study of Atezolizumab With or Without Tiragolumab (Anti-TIGIT Antibody) in Patients With Unresectable Esophageal Squamous Cell Carcinoma Whose Cancers Have Not Progressed Following Definitive Concurrent Chemoradiotherapy

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT04543617
• Other study ID #: YO42137
• Secondary ID: 2020-001178-31
• Status: Active, not recruiting
• Phase: Phase 3
• Start date: September 28, 2020
• Est. completion date: March 31, 2027

Study information

• Verified date: April 2024
• Source: Hoffmann-La Roche
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The purpose of this study is to evaluate the efficacy and safety of tiragolumab plus atezolizumab compared with placebo in participants with unresectable esophageal squamous cell carcinoma (or those who are unable or unwilling to undergo surgery) and whose cancers have not progressed following definitive concurrent chemoradiotherapy (dCRT). Participants will be randomized in a 1:1:1 ratio to receive either tiragolumab plus atezolizumab (Arm A), tiragolumab matching placebo plus atezolizumab (Arm B), or double placebo (Arm C).

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 760
• Est. completion date: March 31, 2027
• Est. primary completion date: March 31, 2027
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Key Inclusion Criteria:

• Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1

• Histologically or cytologically confirmed diagnosis of squamous cell carcinoma of the esophagus

• Unresectable disease ineligible for curative surgery based on the documented opinion of the qualified medical, surgical or radiation oncologist prior to dCRT and is not expected to undergo tumor resection during the course of the study

• dCRT treatment according to regional oncology guidelines for esophageal cancer

• Representative archival formalin-fixed, paraffin-embedded (FFPE) tumor specimens collected prior to initiation of dCRT

• Adequate hematologic and end-organ function prior to randomization

• Women of childbearing potential must remain abstinent or use contraceptive methods with a failure rate of < 1% per year during the treatment period, for 5 months after the final dose of atezolizumab/placebo, and for 90 days after the final dose of tiragolumab/placebo, whichever is later

• Men must agree to remain abstinent (refrain from heterosexual intercourse) or use a condom, and agree to refrain from donating sperm during the treatment period and for 90 days after the final dose of tiragolumab/placebo.

Key Exclusion Criteria:

• Prior treatment with CD137 agonists or immune checkpoint blockade therapies, including anti-CTLA-4, anti-PD-1, anti-PD-L1 and anti-TIGIT therapeutic antibodies

• Any unresolved toxicity of National Cancer Institute's (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Grade = 2 from the prior chemoradiation therapy with the exception of irreversible and manageable hearing loss

• Prior allogeneic stem cell or solid organ transplantation

• Active or history of autoimmune disease or immune deficiency

• History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis

• Malignancies other than esophageal cancer within 2 years prior to screening, with the exception of malignancies with a negligible risk of metastasis or death

• Treatment with any other investigational agent, including epidermal growth factor receptor (EGFR) inhibitors, with therapeutic intent for esophageal cancer prior to randomization.

Related Conditions & MeSH terms

• Carcinoma
• Carcinoma, Squamous Cell
• Esophageal Squamous Cell Carcinoma

Intervention

Drug:
• Tiragolumab
Tiragolumab at a fixed dose of 600 milligrams (mg) administered by intravenous (IV) infusion every 3 weeks (Q3W) on Day 1 of each 21-day cycle.
• Atezolizumab
Atezolizumab at a fixed dose of 1200 mg administered by IV infusion Q3W on Day 1 of each 21-day cycle.
• Tiragolumab Matching Placebo
Tiragolumab matching placebo administered by IV infusion Q3W on Day 1 of each 21-day cycle.
• Atezolizumab Matching Placebo
Atezolizumab matching placebo administered by IV infusion Q3W on Day 1 of each 21-day cycle.

Locations

Country	Name	City	State
Argentina	Fundacion Favaloro	Buenos Aires
Argentina	Instituto de Investigaciones Metabolicas (Idim)	Ciudad Autonoma de Buenos Aires
Argentina	Centro Oncologico Riojano Integral (CORI)	La Rioja
Australia	Austin Health; Cancer Clinical Trial Centre	Heidelberg	Victoria
Australia	St John of God Hospital; Bendat Cancer Centre	Subiaco	Western Australia
Australia	Princess Alexandra Hospital	Woolloongabba	Queensland
Austria	Tiroler Landeskrankenanstalten Ges.M.B.H.; Innere Medizin Abt. Für Hämatologie & Onkologie	Innsbruck
Austria	Klinikum Klagenfurt am Wörthersee; Abteilung für Innere Medizin und Onkologie	Klagenfurt am Wörthersee
Austria	Ordensklinikum Linz Barmherzige Schwestern; Viszeralonkologisches Zentrum	Linz
Austria	AKH - Medizinische Universität Wien; Department for Internal Medicine I	Wien
Belgium	UZ Antwerpen	Edegem
Belgium	UZ Leuven Gasthuisberg	Leuven
Belgium	CHU Sart-Tilman	Liège
China	Anyang Tumor Hosptial	Anyang City
China	Cancer Hospital Chinese Academy of Medical Sciences.	Beijing
China	Affiliated Hospital of Bengbu Medical College	Bengbu
China	Hunan Cancer Hospital	Changsha CITY
China	Heping Hospital Affiliated to Changzhi Medical College	Changzhi City
China	Changzhou Cancer hospital	Changzhou
China	Sichuan Provincial Cancer Hospital	Chengdu
China	West China Hospital, Sichuan University	Chengdu
China	Chongqing Cancer Hospital	Chongqing
China	Chongqing Sanxia Central Hospital	Chongqing City
China	Fujian Cancer Hospital	Fuzhou
China	Nanfang Hospital, Southern Medical University	Guangzhou
China	Sun Yet-sen University Cancer Center	Guangzhou City
China	The First Affiliated Hospital of College of Medicine, Zhejiang University	Hangzhou
China	Affiliated Drum Tower Hospital of Nanjing University Medical School; Nanjing Shi	Jiangsu Sheng
China	Jieyang People's Hospital	Jieyang City
China	Shandong Cancer Hospital	Jinan
China	Affiliated Hospital of Jining Medical University	Jining
China	The First People's Hospital of Lian Yun Gang	Lianyungang
China	Lishui Central Hospital	Lishui City
China	The First Affiliated Hospital to Henan University of Science and Technology	Luoyang City
China	Jiangsu Cancer Hospital	Nanjing City
China	Shanghai Chest Hospital	Shanghai
China	Fudan University Shanghai Cancer Center; Medical Oncology	Shanghai City
China	Cancer Hospital of Shantou University Medical College	Shantou
China	Liaoning cancer Hospital & Institute	Shenyang
China	Cancer Hospital Chinese Academy of Medical Sciences Shenzhen Center	Shenzhen City
China	Hebei Medical University Fourth Hospital;(Tumor Hospital of Hebei Province)	Shijiazhuang
China	Tianjin Cancer Hospital	Tianjin
China	Hubei Cancer Hospital	Wuhan
China	Wuhan Union Hospital Tongji Medical College, Huazhong University of Science and Technology	Wuhan City
China	The First Affiliated Hospital of Xiamen University	Xiamen
China	Zhongshan Hospital Xiamen University	Xiamen
China	The First Affiliated Hospital of Xinxiang Medical University	Xinxiang City
China	The Affiliated Hospital of Xuzhou Medical College	Xuzhou
China	Subei People's Hospital of Jiangsu province; Respiratory	Yangzhou City
China	Zhejiang Cancer Hospital	Zhejiang
France	CHRU De Brest - Hopital Morvan - Institut De Cancerologie Et D'Hematologie	Brest
France	CHU Dijon Bourgogne Hôpital François Mitterand	Dijon
France	Hopital Claude Huriez; Medecine Interne Oncologie	Lille
France	CENTRE LEON BERARD; Département d?Hématologie et d?Oncologie	Lyon
France	Hopital Timone Adultes; Oncologie Digestive	Marseille
France	Centre Antoine Lacassagne	Nice
France	European Hospital Georges Pompidou (HEGP)	Paris
France	Hopital Du Haut-Leveque; Gastro-Enterologie	Pessac
France	Chu La Miletrie; Gastro Enterologie Endoscopies	Poitiers
France	Hopital Rangueil; Gastro Enterologie Et Nutrition	Toulouse
Germany	Kliniken Essen-Mitte, Evang. Huyssens-Stiftung, Klinik für Internistische Onkologie / Haematologie	Essen
Germany	Universitätsklinikum Essen Klinik f.Strahlentherapie	Essen
Germany	Klinik für Gastroenterologie und Gastrointestinale Onkologie der UMG	Göttingen
Germany	Universitaetsklinikum Leipzig	Leipzig
Germany	Med. Fak. d. Otto-von-Guericke-Universität; Unik. für Gastroenter., Hepat. und Infekt.	Magdeburg
Germany	Klinikum der Philipps-Universität Marburg	Marburg
Germany	Universitätsklinikum Klinik u.Poliklinik f.Strahlentherapie	Regensburg
Greece	Evgenidio Hospital "Agia Trias"	Athens
Greece	Univ General Hosp Heraklion; Medical Oncology	Heraklion
Greece	Euromedical General Clinic of Thessaloniki; Oncology Department	Thessaloniki
Hungary	Pécsi Tudományegyetem; Klinikai Központ Onkoterápiás Intézet	Pécs
Hungary	Szegedi Tudományegyetem; Onkoterápiás Klinika	Szeged
Israel	Hadassah Ein Karem Hospital; Oncology Dept	Jerusalem
Israel	Rambam Health Corporation; Oncology Institute	Rambam
Israel	Tel Aviv Sourasky Medical Ctr; Oncology	Tel Aviv
Italy	Ospedale Degli Infermi - Faenza; Oncologia Medica	Faenza	Emilia-Romagna
Italy	Università degli Studi della Campania Luigi Vanvitelli; Divsione Di Oncologia Medica	Napoli	Campania
Italy	Istituto Oncologico Veneto IRCCS	Padova	Veneto
Italy	AUSL-IRCCS di Reggio Emilia; Oncologia Medica	Reggio Emilia	Emilia-Romagna
Italy	ASU FC S. M. DELLA MISERICORDIA; Oncologia	Udine	Friuli-Venezia Giulia
Japan	Aichi Cancer Center Hospital	Aichi
Japan	National Cancer Center Hospital East	Chiba
Japan	Hiroshima University Hospital	Hiroshima
Japan	Kobe University Hospital	Hyogo
Japan	Kanagawa Cancer Center	Kanagawa
Japan	Yokohama City University Medical Center	Kanagawa
Japan	Tohoku University Hospital	Miyagi
Japan	Niigata Cancer Center Hospital	Niigata
Japan	Osaka International Cancer Institute	Osaka
Japan	Osaka University Hospital	Osaka
Japan	Saitama Cancer Center	Saitama
Japan	Saitama Medical University International Medical Center	Saitama
Japan	Shizuoka Cancer Center	Shizuoka
Japan	Keio University Hospital	Tokyo
Japan	The Cancer Institute Hospital of JFCR	Tokyo
Kenya	International Cancer Institute (ICI)	Eldoret
Kenya	Aga Khan University Hospital	Nairobi
Korea, Republic of	Kyungpook National University Chilgok Hospital	Daegu
Korea, Republic of	Ajou University Medical Center	Gyeonggi-do
Korea, Republic of	Chonnam National University Hwasun Hospital	Jeollanam-do
Korea, Republic of	Asan Medical Center	Seoul
Korea, Republic of	Korea University Guro Hospital	Seoul
Korea, Republic of	Samsung Medical Center	Seoul
Korea, Republic of	Severance Hospital, Yonsei University Health System	Seoul
Morocco	Centre Hospitalier Universitaire Hassan II	FES
Morocco	Centre Hospitalier Universitaire Mohamed VI; Oncologie-Hématologie	Marrakech
Morocco	Clinique specialise Menara; Oncology Medical	Marrakech
Morocco	Institut National D'oncologie Sidi Med Benabdellah; Oncolgy Medical	Rabat
New Zealand	Tauranga Hospital, Clinical Trials Unit; BOP Clinical School	Tauranga
Poland	Centrum Onkologii;Im. Franciszka Lukaszczyka;Onkologii	Bydgoszcz
Poland	CENTRUM ONKOLOGII ZIEMI LUBELSKIEJ IM. ?W. JANA Z DUKLI; II Oddzia? Onkologii Klinicznej	Lublin
Poland	Szpital Kliniczny MSWiA z Warmi?sko-Mazurskim Centrum Onkologii; ZAK?.I O.KLINICZNY RADIOTERAPII	Olsztyn
Poland	Wielkopolskie Centrum Onkologii im. Marii Sk?odowskiej-Curie; Odd. Onk. Klin. i Immunoonk.	Pozna?
Poland	NIO im Marii Sklodowskiej-Curie; Klinika Onkologii i Radioterapii	Warszawa
Poland	Dolno?l?skie Centrum Onkologii; Oddzia? Onkologii Klinicznej i Chemioterapii	Wroc?aw
Portugal	HUC; Servico de Oncologia Medica	Coimbra
Portugal	Centro Hospitalar do Porto ? Hospital de Santo António; Oncologia	Porto
Portugal	IPO do Porto; Servico de Oncologia Medica	Porto
Russian Federation	City Oncological Hospital	Izhevsk	Udmurtija
Russian Federation	Republican Clinical Oncology Dispensary of Ministry of Healthcare of Tatarstan Republic	Kazan	Tatarstan
Russian Federation	Krasnoyarsk Regional Oncology Dispensary n.a. Krizhanovsky; Chemotherapy	Krasnoyarsk	Krasnodar
Russian Federation	Russian Oncology Research Center n.a. N.N. Blokhin Dpt of Clinical Pharmacology and Chemotherapy	Moscow	Moskovskaja Oblast
Russian Federation	Limited Liability Company "RC Medical"	Novosibirsk
Russian Federation	Scientific Research Institute n.a. N.N. Petrov	Saint Petersburg	Sankt Petersburg
Russian Federation	SBEI HPE "The First St.Petersburg State Medical University n.a. acad. I.P.Pavlova"of MoH of RF	Sankt-peterburg	Sankt Petersburg
Russian Federation	Regional Oncology Dispensary	Tomsk
South Africa	Wits Donald Gordon Clinical Trial Site	Johannesburg
South Africa	Limpopo Cancer Research Institute	Polokwane
South Africa	Cancercare	Port Elizabeth
South Africa	Eugene Marais Hospital; Oncology	Pretoria
Spain	Complejo Hospitalario Universitario A Coruña (CHUAC); Servicio de Oncologia	A Coruña	LA Coruña
Spain	Hospital Clinic I Provincial	Barcelona
Spain	Hospital Universitari Vall d'Hebron	Barcelona
Spain	Hospital Universitario Reina Sofia	Cordoba
Spain	Fundacion Jimenez Diaz; Servicio de Oncologia	Madrid
Spain	Hospital Regional Universitario Carlos Haya	Malaga
Spain	Hospital Univ. Central de Asturias	Oviedo	Asturias
Spain	Hospital Clinico Universitario de Valencia	Valencia
Spain	Hospital La Fe	Valencia
Switzerland	Inselspital Bern, Insel-Gruppe AG	Bern
Switzerland	UniversitätsSpital Zürich; Zentrum für Hämatologie und Onkologie, Klinik für Onkologie	Zürich
Taiwan	Chang Gung Medical Foundation - Kaohsiung; Oncology; Division of Hematology-Oncology	Kaoisung
Taiwan	China Medical University Hospital; Oncology and Hematology	Taichung
Taiwan	Chi-Mei Medical Centre; Hematology & Oncology	Tainan
Taiwan	National Cheng Kung University Hospital; Oncology	Tainan
Taiwan	Taipei Veterans General Hospital; Department of Oncology	Taipei City
Taiwan	National Taiwan University Hospital; Oncology	Zhongzheng Dist.
Thailand	Chulalongkorn Hospital; Medical Oncology	Bangkok
Thailand	Ramathibodi Hospital; Dept of Med.-Div. of Med. Onc	Bangkok
Thailand	Siriraj Hospital; Medical Oncology Unit	Bangkok
Thailand	Vajira Hospital	Bangkok
Thailand	Songklanagarind Hospital; Department of Oncology	Songkhla
Turkey	Baskent University Adana Dr. Turgut Noyan Practice and Research Hospital; Medical Oncology	Adana
Turkey	Ankara City Hospital; Oncology	Ankara
Turkey	Ankara University Faculty of Medicine Cebeci Hospital	Ankara
Turkey	Ataturk University Medical Faculty Yakutiye Research Hospital Medical Oncology Department	Erzurum
Turkey	Istanbul University Cerrahpa?a-Cerrahpa?a Medical Faculty; Medikal Onkoloji Departmani	Istanbul
Turkey	Goztepe Prof.Dr. Suleyman Yalcin City Hospital; Clinical Oncology	Kadiköy
Turkey	Inonu University Faculty of Medicine Turgut Ozal Medical Center; Onkoloji, Elazig Yolu,	Malatya
Turkey	Van Yuzuncu Yil University Hospital; Medical Oncology	Van
Ukraine	Municipal Noncommercial Institution Regional Center of Oncology	Kharkiv	Kharkiv Governorate
Ukraine	RCI Sumy Regional Clinical Oncological Dispensary	Sumy
Ukraine	Vinnytsya Regional Clinical Oncology Dispensary	Vinnytsya	Podolia Governorate
Ukraine	Zhytomyr Regional Oncology Center	Zhytomyr	KIEV Governorate
United Kingdom	Royal Bournemouth Hospital; Oncology	Bournemouth
United Kingdom	Addenbrookes Hospital; Cambridge Cancer Trials Centre, S4 Box 279	Cambridge
United Kingdom	Ninewells Hospital; Oncology	London
United Kingdom	Royal Marsden Hospital - Fulham; Oncology Department	London
United Kingdom	Royal Marsden Hospital (Sutton)	Sutton
United Kingdom	Clatterbridge Cancer Centre	Wirral
United Kingdom	New Cross Hospital	Wolverhampton
United States	Compassionate Cancer Care Medical Group, Inc	Corona	California
United States	Compassionate Care Research Group Inc. Corona	Corona	California
United States	Florida Cancer Specialists - Fort Myers (Broadway)	Fort Myers	Florida
United States	MD Anderson Cancer Center; Oncology	Houston	Texas
United States	Mount Sinai Medical Center	New York	New York
United States	Weill Cornell Medical College	New York	New York
United States	Compassionate Care Research Group Inc. Riverside	Riverside	California
United States	Florida Cancer Specialist, North Region	Saint Petersburg	Florida
United States	Great Lakes Cancer Center	Williamsville	New York

Sponsors (1)

Lead Sponsor	Collaborator
Hoffmann-La Roche

Countries where clinical trial is conducted

United States,  Argentina,  Australia,  Austria,  Belgium,  China,  France,  Germany,  Greece,  Hungary,  Israel,  Italy,  Japan,  Kenya,  Korea, Republic of,  Morocco,  New Zealand,  Poland,  Portugal,  Russian Federation,  South Africa,  Spain,  Switzerland,  Taiwan,  Thailand,  Turkey,  Ukraine,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Arm A vs Arm C: Investigator-Assessed Progression-Free Survival (PFS)		From randomization to the first occurrence of disease progression or death from any cause, whichever occurs first (up to approximately 6 years)
Primary	Arm A vs Arm C: Overall Survival (OS)		From randomization to death from any cause (up to approximately 6 years)
Primary	Arm B vs Arm C: OS		From randomization to death from any cause (up to approximately 6 years)
Secondary	Arm B vs Arm C: Investigator-Assessed PFS		From randomization to the first occurrence of disease progression or death from any cause, whichever occurs first (up to approximately 6 years)
Secondary	Arm A vs Arm B: Investigator-Assessed PFS		From randomization to the first occurrence of disease progression or death from any cause, whichever occurs first (up to approximately 6 years)
Secondary	Arm A vs Arm B: OS		From randomization to death from any cause (up to approximately 6 years)
Secondary	Independent Review Facility (IRF)-Assessed PFS		From randomization to the first occurrence of disease progression or death from any cause, whichever occurs first (up to approximately 6 years)
Secondary	Investigator-Assessed Confirmed Objective Response Rate (ORR)		From randomization up to approximately 6 years
Secondary	IRF-Assessed Confirmed ORR		From randomization up to approximately 6 years
Secondary	Investigator-Assessed Duration of Objective Response (DOR)		From the first occurrence of a documented confirmed objective response to the first occurrence of disease progression or death from any cause, whichever occurs first (up to approximately 6 years)
Secondary	IRF-Assessed DOR		From the first occurrence of a documented confirmed objective response to the first occurrence of disease progression or death from any cause, whichever occurs first (up to approximately 6 years)
Secondary	Percentage of Participants With Clinically Meaningful Changes in Physical Functioning, Role Functioning, Quality of Life (QoL) as Measured by EORTC QLQ-C30	Clinically meaningful changes in physical functioning, role functioning, global health status (GHS)/QoL as measured by the European Organisation for Research and Treatment of Cancer Quality of Life-Core 30 Questionnaire (EORTC QLQ-C30). EORTC QLQ-C30 is a self-reported measure, consisting of 30 questions that assess 5 aspects of participants functioning (physical, emotional, role, cognitive and social), 3 symptom scales (fatigue, nausea and vomiting, and pain), GHS and QoL, and 6 single items (dyspnea, insomnia, appetite loss, constipation, diarrhea and financial difficulties) within the previous week. Functioning and symptoms items are scored on a 4-point scale: 1=Not at all, 2=A little, 3=Quite a bit, 4=Very much. GHS and QoL items are scored on a 7-point scale: 1=Very poor, 2, 3, 4, 5, 6, 7=Excellent. Scores will be linearly transformed to a range of 0 to 100, with higher scores (i.e. closer to 100) reflecting better functioning, better GHS/QoL, and worse symptoms.	Up to approximately 6 years
Secondary	Percentage of Participants With Clinically Meaningful Changes in Dysphagia as Measured by EORTC QLQ-OES18	Clinically meaningful changes in dysphagia as measured by the EORTC Quality of Life-Esophageal Cancer, Module 18 Questionnaire (EORTC QLQ-OES18). EORTC QLQ-OES18 is a modular supplement to the EORTC QLQ-C30 questionnaire for use in participants with esophageal cancer. EORTC QLQ-OES18 consists of 4 multiple-item scale (dysphagia, eating, reflux, and pain) and 6 single items (trouble swallowing saliva, choked when swallowing, dry mouth, trouble with taste, trouble with coughing, and trouble talking) with a recall period of the previous week. Each symptom item is scored on a 4-point scale: 1=Not at all, 2=A little, 3=Quite a bit, 4=Very much. Scores will be linearly transformed to a range of 0 to 100, with higher transformed scores (i.e. closer to 100) reflecting worse symptoms.	Up to approximately 6 years
Secondary	Percentage of Participants With Adverse Events (AEs)		Up to approximately 6 years
Secondary	Serum Concentration of Tiragolumab		Predose and postdose on Day 1 of Cycle 1 (each cycle=21 days) and predose on Day 1 of Cycles 2, 3, 4, 8, 12 and 16 and at treatment discontinuation (TD) visit (up to approximately 6 years)
Secondary	Serum Concentration of Atezolizumab		Predose and postdose on Day 1 of Cycle 1 (each cycle=21 days) and predose on Day 1 of Cycles 2, 3, 4, 8, 12 and 16 and at TD visit (up to approximately 6 years)
Secondary	Percentage of Participants With Anti-drug Antibodies (ADAs) to Tiragolumab		Predose on Day 1 of Cycles (each cycle=21 days) 1, 2, 3, 4, 8, 12 and 16 and at TD visit (up to approximately 6 years)
Secondary	Percentage of Participants With ADAs to Atezolizumab		Predose on Day 1 of Cycles (each cycle=21 days) 1, 2, 3, 4, 8, 12 and 16 and at TD visit (up to approximately 6 years)