Multicenter Study of Rociletinib Administered to Patients With Previously Treated Mutant EGFR Non-small Cell Lung Cancer

Non-small Cell Lung Cancer Clinical Trial

— NSCLC  

Official title:

TIGER-2: A Phase 2, Open-label, Multicenter, Safety and Efficacy Study of Oral CO-1686 as 2nd Line EGFR-directed TKI in Patients With Mutant EGFR Non-small Cell Lung Cancer (NSCLC)

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT02147990
• Other study ID #: CO-1686-019 (TIGER-2)
• Status: Terminated
• Phase: Phase 2
• Start date: June 16, 2014
• Est. completion date: August 27, 2019

Study information

• Verified date: July 2020
• Source: Clovis Oncology, Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The purpose of this study is to evaluate the safety and anti-tumor effect of rociletinib. The trial is open-ended, which means patients will continue to take rociletinib until the study doctor determines it is no longer beneficial for them.

Description:

This is a Phase 2, single arm, open-label, dual cohort, multicenter study evaluating the safety and efficacy of rociletinib administered orally to patients with previously treated mutant EGFR NSCLC.

Patients will be enrolled into 2 cohorts. Cohort A will enroll approximately 125 eligible patients who are centrally confirmed T790M-positive. Cohort B will be a continuation of the study and will enroll up to approximately 100 eligible patients who will be either centrally confirmed T790M-positive or T790M-negative.

All patients (for Cohort A and B) should have experienced disease progression while on treatment with the first single-agent EGFR-directed TKI (EGFR-TKI) for advanced/metastatic NSCLC. One line of chemotherapy prior to the EGFR-TKI treatment is permissible.

The study (Cohorts A and B) will consist of a screening phase to establish study eligibility and document baseline measurements, an open-label treatment phase, in which the patient will receive rociletinib to ascertain safety and efficacy until disease progression as defined by RECIST Version 1.1, clinical tumor progression, or unacceptable toxicity as assessed by the investigator. For patients with clinical progression, radiographic assessment should be performed to document evidence of radiographic progression.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 318
• Est. completion date: August 27, 2019
• Est. primary completion date: July 30, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria

• Histologically or cytologically confirmed metastatic or unresectable locally advanced NSCLC

• Documented evidence of a tumor with 1 or more EGFR mutations excluding exon 20 insertion

• Disease progression confirmed by radiologic assessment while receiving treatment with the first single agent EGFR-TKI

• EGFR TKI treatment discontinued less than or equal to 30 days prior to planned initiation of rociletinib

• The washout period for an EGFR inhibitor is a minimum of 3 days

• No intervening treatment between cessation of single agent EGFR TKI and planned initiation of rociletinib

• Previous treatment with less than or equal to 1 prior chemotherapy (excluding prior neo-adjuvant or adjuvant chemotherapy or chemoradiotherapy with curative intent)

• Any toxicity related to prior EGFR inhibitor treatment must have resolved to Grade 1 or less

• Central laboratory confirmation of the presence of the T790M mutation in tumor tissue in Cohort A and the presence or absence of the T790M mutation in tumor tissue in Cohort B. Centrally indeterminate, unknown or invalid specimens are not acceptable. Biopsy material obtained from either primary or metastatic tumor tissue and sent to the central laboratory must be within 60 prior to dosing study drug but following disease progression on the first EGFR TKI

• Measurable disease according to RECIST Version 1.1

• Life expectancy of at least 3 months

• ECOG performance status of 0 to 1

• Minimum Age 18 years (in certain territories, the minimum age requirement may be higher eg age 20 years in Japan and Taiwan)

• Adequate hematological and biological function, confirmed by defined laboratory values

• Written consent on an IRB/IEC-approved Informed Consent Form (ICF) prior to any study specific evaluation

Exclusion Criteria

• Documented evidence of an exon 20 insertion activating mutation in the EGFR gene

• Active second malignancy i.e. patient known to have potentially fatal cancer present for which he/she may be (but not necessarily) currently receiving treatment

• Patients with a history of malignancy that has been completely treated, with no evidence of that cancer currently, are permitted to enrol in the trial provided all chemotherapy was completed greater than 6 months prior and/or bone marrow transplant greater than 2 years prior

• Known pre-existing interstitial lung disease

• Cohort A only: Patients with leptomeningeal carcinomatosis are excluded. Other central nervous system (CNS) metastases are only permitted if treated, asymptomatic, and stable (not requiring steroid for at least 4 weeks prior to the start of study treatment). Cohort B only: Patients with CNS metastases or leptomeningeal carcinomatosis are excluded.

• Treatment with prohibited medications less than or equal to 14 days prior to treatment with rociletinib

• Patients who are currently receiving treatment with any medications that have the potential to prolong the QT interval and the treatment cannot be either discontinued or switched to a different medication before starting rociletinib

• Prior treatment with rociletinib, or other drugs that target T790M positive mutant EGFR with sparing of wild type EGFR

• Any of the following cardiac abnormalities or history

• Clinically significant abnormal 12-lead ECG, QT interval corrected using Fridericia's method (QTCF) greater than 450 msec

• Inability to measure QT interval on ECG

• Personal or family history of long QT syndrome

• Implantable pacemaker or implantable cardioverter defibrillator

• Resting bradycardia less than 55 beats/min

• Non-study related surgical procedures less than or equal to 7 days prior to administration of rociletinib. In all cases, the patient must be sufficiently recovered and stable before treatment administration

• Females who are pregnant or breastfeeding

• Refusal to use adequate contraception for fertile patients (females and males) while on treatment and for 12 weeks after the last dose of rociletinib

• Presence of any serious or unstable concomitant systemic disorder incompatible with the clinical study

• Any other reason the investigator considers the patient should not participate in the study

Related Conditions & MeSH terms

• Carcinoma, Non-Small-Cell Lung
• Lung Neoplasms
• Non-small Cell Lung Cancer

Intervention

Drug:
• Rociletinib
Rociletinib will be administered to patients orally

Locations

Country	Name	City	State
Australia	Flinders Medical Centre	Bedford Park	South Australia
Australia	Icon Cancer Centre	South Brisbane	New South Wales
Australia	Royal North Shore Hospital	Sydney	New South Wales
Australia	Westmead Hospital	Westmead	New South Wales
Canada	Princess Margaret Hospital	Toronto	Ontario
France	Centre Hospitalier Regional Universitaire (CHRU) de Besancon - L'Hopital Jean Minjoz	Besançon	Franche-comte
France	Centre Hospitalier Universitaire Côte de Nacre	Caen
France	Centre Hospitalier Universitaire Hôpital Nord	Marseille Cedex 20
France	Hôpital Tenon	Paris	Ile-de-france
France	Centre Hospitalier Lyon Sud	Pierre Bénité cedex	Rhone-alpes
France	Institut de Cancérologie de l'Ouest - René Gauducheau	Saint Herblain cedex	PAYS DE LA Loire
France	Institut Gustave Roussy	Villejuif	Ile-de-France
Germany	Evangelische Lungenklinik Berlin	Berlin
Germany	Universitaetsklinikum Bonn - Zentrum fuer Innere Medizin - Medizinische Klinik und Poliklink III	Bonn	Nordrhein-westfalen
Germany	Universitätsklinikum Essen	Essen	Nordrhein-westfalen
Germany	Goethe-Universität Frankfurt am Main	Frankfurt am Main	Hessen
Germany	Asklepios Fachkliniken München-Gauting	Gauting	Bayern
Germany	LungenClinic Großhansdorf GmbH	Großhansdorf	Schleswig-holstein
Germany	Universitätsklinikum Köln	Köln	Nordrhein-westfalen
Germany	Klinikum Innenstadt LMU	München	Bayern
Germany	Pius Hospital Oldenburg	Oldenburg	Niedersachsen
Hong Kong	Queen Mary Hospital	Hong Kong
Korea, Republic of	Dong-A University Hospital	Busan
Korea, Republic of	Chungbuk National University Hospital	Chungju	Chungcheongbuk-do
Korea, Republic of	National Cancer Center	Goyang-si	Gyeonggi-do
Korea, Republic of	Gachon University Gil Medical Center	Incheon	Gyeonggi-do
Korea, Republic of	Inha University Hospital	Incheon
Korea, Republic of	Asan Medical Center	Seoul
Korea, Republic of	Samsung Medical Center	Seoul
Korea, Republic of	Seoul National University Hospital	Seoul
Korea, Republic of	Seoul Saint Mary's Hospital	Seoul
Korea, Republic of	Severance Hospital, Yonsei University Health System	Seoul
Netherlands	Antoni van Leeuwenhoek Hospital	Amsterdam	Noord-holland
Netherlands	Vrije Universiteit Medisch Centrum	Amsterdam
Spain	Hospital Universitari Germans Trias i Pujol	Badalona
Spain	Hospital Universitario Quirón Dexeus	Barcelona
Spain	Hospital Vall d´Hebrón	Barcelona
Spain	Hospital Universitario La Paz	Madrid
Spain	Hospital Universitario Virgen del Rocio	Seville	Sevilla
Switzerland	Centre Hospitalier Universitaire Vaudoise	Lausanne	Vaud
Taiwan	China Medical University Hospital	Taichung
Taiwan	Taichung Veterans General Hospital	Taichung
Taiwan	National Taiwan University Hospital	Taipei
Taiwan	Taipei Veterans General Hospital	Taipei	Taipei CITY
Taiwan	Chang Gung Memorial Hospital Linkou	Taoyuan	Tao-Yuan
United Kingdom	Cambridge University Hospitals NHS Foundation Trust	Cambridge	England
United Kingdom	Guy's and Saint Thomas NHS Foundation Trust	London	Greater London
United Kingdom	Royal Marsden Hospital	London	Greater London
United Kingdom	University College Hospital	London
United Kingdom	Royal Marsden NHS Trust	Sutton	Surrey
United States	UCLA Medical Center	Alhambra	California
United States	Texas Oncology P.A.	Amarillo	Texas
United States	USO - Texas Oncology P.A.	Arlington	Texas
United States	Texas Oncology-Austin Central	Austin	Texas
United States	Comprehensive Blood and Cancer Center	Bakersfield	California
United States	Texas Oncology-Beaumont	Beaumont	Texas
United States	Texas Oncology P.A.	Bedford	Texas
United States	Beth Israel Comprehensive Cancer Center	Boston	Massachusetts
United States	Montefiore Medical Center	Bronx	New York
United States	Lahey Hospital and Medical Center	Burlington	Massachusetts
United States	Northwestern University Feinberg School of Medicine	Chicago	Illinois
United States	University of Illinois Chicago	Chicago	Illinois
United States	Cleveland Clinic	Cleveland	Ohio
United States	University Hospitals of Cleveland	Cleveland	Ohio
United States	Texas Oncology P.A.	Dallas	Texas
United States	Virginia Cancer Specialists	Fairfax	Virginia
United States	Texas Oncology P.A.	Flower Mound	Texas
United States	Saint Jude Heritage Healthcare	Fullerton	California
United States	Saint Mary's Regional Cancer Center	Grand Junction	Colorado
United States	The Methodist Hospital	Houston	Texas
United States	University of California San Diego Moores Cancer Center	La Jolla	California
United States	New York Oncology Hematology, PC	Latham	New York
United States	Rocky Mountain Cancer Centers, LLP	Lone Tree	Colorado
United States	Advanced Medical Specialties	Miami	Florida
United States	Minnesota Oncology Hematology, P.A	Minneapolis	Minnesota
United States	Tennessee Oncology, PLLC	Nashville	Tennessee
United States	Yale University School of Medicine	New Haven	Connecticut
United States	Illinois Cancer Specialists	Niles	Illinois
United States	Northridge Hospital Medical Center	Northridge	California
United States	Fox Chase Cancer Center	Philadelphia	Pennsylvania
United States	Texas Oncology - Plano East	Plano	Texas
United States	Cancer Care Associates	Redondo Beach	California
United States	Mayo Clinic - Rochester	Rochester	Minnesota
United States	University of Rochester	Rochester	New York
United States	University of California Davis Medical Center	Sacramento	California
United States	Washington University School of Medicine	Saint Louis	Missouri
United States	University of California San Francisco	San Francisco	California
United States	Coastal Integrative Cancer Care	San Luis Obispo	California
United States	Northwest Cancer Specialists, P.C.	Vancouver	Washington
United States	Cleveland Clinic Florida	Weston	Florida
United States	Yakima Valley Memorial Hospital, North Star Lodge	Yakima	Washington

Sponsors (1)

Lead Sponsor	Collaborator
Clovis Oncology, Inc.

Countries where clinical trial is conducted

United States,  Australia,  Canada,  France,  Germany,  Hong Kong,  Korea, Republic of,  Netherlands,  Spain,  Switzerland,  Taiwan,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Objective Response Rate (ORR) According to RECIST Version 1.1 as Determined by Investigator Assessment	ORR is defined as the percentage of patients with a best overall confirmed response of partial response (PR) or complete response (CR) recorded from the start of the treatment until disease progression. For patients who continued treatment post-progression, the first date of progression was used for the analysis. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions, defined by and assessed as: Complete Response (CR), is disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to < 10 mm. Partial Response (PR), at least a 30% decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum of longest diameter.	Cycle 1 Day 1 to End of Treatment, up to approximately 57 months.
Secondary	Duration of Response (DOR) in T790M Positive Patients According to RECIST Version 1.1 as Determined by Investigator Assessment	DOR in patients with a T790M mutation (determined by central lab) with confirmed response per investigator. The DOR for complete response (CR) and partial response (PR) was measured from the date that any of these best responses is first recorded until the first date that progressive disease (PD) is objectively documented. For patients who continue treatment post-progression, the first date of progression was used for the analysis.	From Cycle 1 Day 1 until disease progression or end of treatment, whichever came first, assessed up to 54 months
Secondary	Disease Control Rate (DCR) by RECIST v1.1 as Determined by Investigator Assessment	DCR is defined as the percentage of patients who have achieved CR, PR, and SD lasting at least 12 weeks. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions, defined by and assessed as: Complete Response (CR), is disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to < 10 mm. Partial Response (PR), at least a 30% decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum of longest diameter. Stable Disease (SD), neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD), taking as reference the smallest sum longest diameter since the treatment started.	From Cycle 1 Day 1 until disease progression or end of treatment, whichever came first, assessed up to 57 months
Secondary	Progression-free Survival (PFS) in T790M Positive Patients by RECIST v1.1 as Determined by Investigator Assessment	PFS was calculated as 1+ the number of days from the first dose of study drug to documented radiographic progression or death due to any cause, whichever occurs first. Patients without a documented event of radiographic progression were censored on the date of their last adequate tumor assessment (i.e., radiologic assessment) or date of first dose of study drug if no tumor assessments were performed. For patients who continued treatment post-progression, the first date of progression was used for the analysis of PFS. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), at least a 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions is also considered progression.	From Cycle 1 Day 1 until disease progression or end of treatment, whichever came first, assessed up to 57 months
Secondary	Overall Survival (OS) Determined by Investigator Assessment	OS was calculated as 1+ the number of days from the first dose of study drug to death due to any cause. Patients without a documented date of death will be censored on the date the patient was last known to be alive.	Cycle 1 Day 1 to date of death, assessed up to 57 months
Secondary	Change From Baseline to Cycles 5, 10 and End of Treatment (EOT) in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire for Patients With Cancer (EORTC QLQ-C30) Global Health Status Quality of Life Scale	EORTC QLC-C30 is a 30-item questionnaire to assess the quality of life in cancer patients. EORTC QLQ-C30 includes functional scales (physical, role, cognitive, emotional, social), global health status, symptom scales (fatigue, pain, nausea/vomiting), and other (dyspnoea, appetite loss, insomnia, constipation/diarrhea, financial difficulties). Most questions used 4-point scale (1 'Not at All' to 4 'Very Much'); two used 7-point scale (1 'Very Poor' to 7 'Excellent'). Scores are averaged, and transformed to 0-100 scale; higher score = better quality of life.	Baseline (Day 0), Months 5, 10 and EOT
Secondary	Change From Baseline to Cycles 5, 10 and End of Treatment (EOT) in Dermatology Life Quality Index (DLQI)	Dermatology Life Quality Index (DLQI) score is a participant-reported outcome consisting of a set of 10 questions regarding the degree to which the participant's skin has affected certain behaviors and quality of life over the last week. Responses to each are: very much (score of 3), a lot, a little, or not at all (score of 0). The DLQI score ranges from 0 (best) to 30 (worst); the higher the score, the more quality of life is impaired.	Baseline (Day 0), Months 5, 10 and EOT
Secondary	Change From Baseline to Cycles 5, 10 and End of Treatment (EOT) in EORTC QLQ-LC-13 Alopecia Scale	EORTC QLQ-LC13 is the lung cancer module of EORTC QLQ-C30 and includes questions specific to the disease associated symptoms (dyspnea, cough, hemoptysis, and site specific pain), treatment-related symptoms (sore mouth, dysphagia, neuropathy and alopecia), and analgesic use of lung cancer patients. The scale was transformed to a range of 0 to 100 using standard EORTC algorithm. Higher score indicates worse symptoms.	Baseline (Day 0), Months 5, 10 and EOT
Secondary	Change From Baseline to Cycles 5, 10 and End of Treatment (EOT) in EORTC QLQ-LC-13 Coughing Scale	EORTC QLQ-LC13 is the lung cancer module of EORTC QLQ-C30 and includes questions specific to the disease associated symptoms (dyspnea, cough, hemoptysis, and site specific pain), treatment-related symptoms (sore mouth, dysphagia, neuropathy and alopecia), and analgesic use of lung cancer patients. The scale was transformed to a range of 0 to 100 using standard EORTC algorithm. Higher score indicates worse symptoms.	Baseline (Day 0), Months 5, 10 and EOT
Secondary	Change From Baseline to Cycles 5, 10 and End of Treatment (EOT) in EORTC QLQ-LC-13 Dysphagia Scale	EORTC QLQ-LC13 is the lung cancer module of EORTC QLQ-C30 and includes questions specific to the disease associated symptoms (dyspnea, cough, hemoptysis, and site specific pain), treatment-related symptoms (sore mouth, dysphagia, neuropathy and alopecia), and analgesic use of lung cancer patients. The scale was transformed to a range of 0 to 100 using standard EORTC algorithm. Higher score indicates worse symptoms.	Baseline (Day 0), Months 5, 10 and EOT
Secondary	Change From Baseline to Cycles 5, 10 and End of Treatment (EOT) in EORTC QLQ-LC-13 Dyspnoea Scale	EORTC QLQ-LC13 is the lung cancer module of EORTC QLQ-C30 and includes questions specific to the disease associated symptoms (dyspnea, cough, hemoptysis, and site specific pain), treatment-related symptoms (sore mouth, dysphagia, neuropathy and alopecia), and analgesic use of lung cancer patients. The scale was transformed to a range of 0 to 100 using standard EORTC algorithm. Higher score indicates worse symptoms.	Baseline (Day 0), Months 5, 10 and EOT
Secondary	Change From Baseline to Cycles 5, 10 and End of Treatment (EOT) in EORTC QLQ-LC-13 Haemoptysis Scale	EORTC QLQ-LC13 is the lung cancer module of EORTC QLQ-C30 and includes questions specific to the disease associated symptoms (dyspnea, cough, hemoptysis, and site specific pain), treatment-related symptoms (sore mouth, dysphagia, neuropathy and alopecia), and analgesic use of lung cancer patients. The scale was transformed to a range of 0 to 100 using standard EORTC algorithm. Higher score indicates worse symptoms.	Baseline (Day 0), Months 5, 10 and EOT
Secondary	Change From Baseline to Cycles 5, 10 and End of Treatment (EOT) in EORTC QLQ-LC-13 Pain in Arm or Shoulder Scale	EORTC QLQ-LC13 is the lung cancer module of EORTC QLQ-C30 and includes questions specific to the disease associated symptoms (dyspnea, cough, hemoptysis, and site specific pain), treatment-related symptoms (sore mouth, dysphagia, neuropathy and alopecia), and analgesic use of lung cancer patients. The scale was transformed to a range of 0 to 100 using standard EORTC algorithm. Higher score indicates worse symptoms.	Baseline (Day 0), Months 5, 10 and EOT
Secondary	Change From Baseline to Cycles 5, 10 and End of Treatment (EOT) in EORTC QLQ-LC-13 Pain in Chest Scale	EORTC QLQ-LC13 is the lung cancer module of EORTC QLQ-C30 and includes questions specific to the disease associated symptoms (dyspnea, cough, hemoptysis, and site specific pain), treatment-related symptoms (sore mouth, dysphagia, neuropathy and alopecia), and analgesic use of lung cancer patients. The scale was transformed to a range of 0 to 100 using standard EORTC algorithm. Higher score indicates worse symptoms.	Baseline (Day 0), Months 5, 10 and EOT
Secondary	Change From Baseline to Cycles 5, 10 and End of Treatment (EOT) in EORTC QLQ-LC-13 Medicine for Pain Scale	EORTC QLQ-LC13 is the lung cancer module of EORTC QLQ-C30 and includes questions specific to the disease associated symptoms (dyspnea, cough, hemoptysis, and site specific pain), treatment-related symptoms (sore mouth, dysphagia, neuropathy and alopecia), and analgesic use of lung cancer patients. The scale was transformed to a range of 0 to 100 using standard EORTC algorithm. Higher score indicates worse symptoms.	Baseline (Day 0), Months 5, 10 and EOT
Secondary	Change From Baseline to Cycles 5, 10 and End of Treatment (EOT) in EORTC QLQ-LC-13 Pain in Other Parts Scale	EORTC QLQ-LC13 is the lung cancer module of EORTC QLQ-C30 and includes questions specific to the disease associated symptoms (dyspnea, cough, hemoptysis, and site specific pain), treatment-related symptoms (sore mouth, dysphagia, neuropathy and alopecia), and analgesic use of lung cancer patients. The scale was transformed to a range of 0 to 100 using standard EORTC algorithm. Higher score indicates worse symptoms.	Baseline (Day 0), Months 5, 10 and EOT
Secondary	Change From Baseline to Cycles 5, 10 and End of Treatment (EOT) in EORTC QLQ-LC-13 Peripheral Neuropathy Scale	EORTC QLQ-LC13 is the lung cancer module of EORTC QLQ-C30 and includes questions specific to the disease associated symptoms (dyspnea, cough, hemoptysis, and site specific pain), treatment-related symptoms (sore mouth, dysphagia, neuropathy and alopecia), and analgesic use of lung cancer patients. The scale was transformed to a range of 0 to 100 using standard EORTC algorithm. Higher score indicates worse symptoms.	Baseline (Day 0), Months 5, 10 and EOT
Secondary	Change From Baseline to Cycles 5, 10 and End of Treatment (EOT) in EORTC QLQ-LC-13 Sore Mouth Scale	EORTC QLQ-LC13 is the lung cancer module of EORTC QLQ-C30 and includes questions specific to the disease associated symptoms (dyspnea, cough, hemoptysis, and site specific pain), treatment-related symptoms (sore mouth, dysphagia, neuropathy and alopecia), and analgesic use of lung cancer patients. The scale was transformed to a range of 0 to 100 using standard EORTC algorithm. Higher score indicates worse symptoms.	Baseline (Day 0), Months 5, 10 and EOT
Secondary	Population PK (POPPK) and Exposure-Response (ER) Analysis of Rociletinib	Sparse blood sampling for POPPK and ER analyses in all patients treated with rociletinib.	Every 4 weeks for approximately 6 months (Day 1 of Cycles 2 to 7 inclusive)