Patients must not have brain metastases unless brain metastases have been treated and patient is asymptomatic with no residual neurological dysfunction and has not received enzyme-reducing anti-epileptic drugs or corticosteroids for at least  days prior to registration
Patients with a history of treated brain metastases who are asymptomatic and have not received steroid therapy in the  days prior to registration are eligible; anti-seizure medications are allowed provided they are non-enzyme inducing (e.g. topiramate, levetiracetam, gabapentin)
Participants may not have clinically symptomatic brain metastases or leptomeningeal disease; patients may be on a stable dose of corticosteroids to control brain metastases if they have been on a stable dose for two weeks ( days) prior to study treatment and are clinically asymptomatic
Patients must not have known brain metastases unless brain metastases have been treated and patient is asymptomatic with no residual neurological dysfunction and has not received enzyme-reducing anti-epileptic drugs or corticosteroids for at least  days prior to registration
Participants with symptomatic uncontrolled brain metastases; baseline brain imaging by CT or MRI is required for all patients; participants with brain metastases that have been treated with prior radiation therapy and are stable on a subsequent scan are allowed; participants with untreated possible brain metastases that are new at the time of screening and are <  cm and asymptomatic are allowed; the participant can receive corticosteroids as long as these were started and at a stable dose at least  days prior to treatment
Symptomatic or unstable brain metastases; (Note: Asymptomatic patients with metastatic brain disease who have been on a stable dose of corticosteroids for treatment of brain metastases for at least  days prior to randomization are eligible to participate in the study)
COHORT A: Previously untreated asymptomatic brain metastases
Participants with untreated brain metastases. Participants with treated metastases that are clinically stable and asymptomatic for at least  weeks and who are off or receiving low-dose corticosteroid treatment (=< mg prednisone or equivalent) for at least  weeks prior to study treatment are eligible
History of central nervous system (CNS) disease; Note: patients with brain metastases will be eligible if treated appropriately and if they remain clinically stable neurologically; for asymptomatic brain metastases, appropriate clinical treatment may include observation with serial imaging
ENROLLMENT TO THE DOSE ESCALATION, EXPANSION AND PART II: Participants with known untreated brain metastases are excluded; patients with a history of brain metastases are permitted to enroll if they have been treated, are no longer taking corticosteroids, and have been stable for a minimum of one month on imaging; exceptions for participants with asymptomatic sub-centimeter metastases that, in the opinion of the treating investigator, do not require intervention may be possible following discussion and agreement with the overall principal investigator
Participants with asymptomatic CNS metastases with previous or concomitant brain deficiencies, as defined in the protocol
Patients with brain metastases which are symptomatic may not be enrolled; those subjects with untreated brain metastases =<  cm may who are asymptomatic and for whom there are no plans for surgery, radiation or corticosteroid use may be considered eligible at the discretion of the principal investigator; subjects with brain metastases that have been treated and are stable for at least  month are eligible if they are asymptomatic and not receiving corticosteroids
Subject has known active central nervous system (CNS) involvement; the subject has untreated brain or meningeal metastases; CT scans are not required to rule out brain or meningeal metastases unless there is a clinical suspicion of central nervous system disease; subjects with treated brain metastases that are radiographically or clinically stable for at least  weeks after therapy and have no evidence of cavitation or hemorrhage in the brain lesion(s) are eligible, providing that they are asymptomatic, and do not require corticosteroids (must have discontinued steroids at least  week prior to study drug administration)
Subjects with symptomatic brain metastases will be excluded from trial secondary to poor prognosis. However, subjects who have asymptomatic brain metastases, and those had treatment for their brain metastasis and whose brain disease is stable without steroid therapy for  weeks may be enrolled (replacement doses =<  mg of prednisone or equivalent per day are allowed)
Subjects with untreated or uncontrolled brain metastases. Patients with asymptomatic brain metastases or previously treated brain metastases that are stable (i.e. not requiring corticosteroids) at the time of study start will be eligible
Patients with untreated or uncontrolled brain metastases or evidence of leptomeningeal disease. Patients with asymptomatic brain metastases or previously treated brain metastases that are stable (i.e. not requiring corticosteroids) at the time of study start will be eligible
COHORT : HORMONE RECEPTOR POSITIVE BREAST CANCER: Patients with symptomatic brain metastases or leptomeningeal involvement; patients with asymptomatic or brain metastases that have been treated with radiation at least  weeks prior to first dose of study treatment are allowed
COHORT : TRIPLE NEGATIVE BREAST CANCER: Patients with symptomatic brain metastases or leptomeningeal involvement; patients with asymptomatic or brain metastases that have been treated with radiation at least  weeks prior to first dose of study treatment are allowed
COHORT : ENDOMETRIAL CANCER: Patients with symptomatic brain metastases or leptomeningeal involvement; patients with asymptomatic or brain metastases that have been treated with radiation at least  weeks prior to first dose of study treatment are allowed
Patients who have known leptomeningeal metastases or untreated or symptomatic brain metastases; treated, asymptomatic brain metastasis can be included
Brain tumors and/or brain metastases unless they are asymptomatic, stable on recent imaging (not dated more than  days from the inclusion date), and have not required active treatment in the last  months
Patients with clinically symptomatic brain metastases or leptomeningeal disease; patients may be on a stable dose of corticosteroids to control brain metastases if they have been on a stable dose for two weeks prior to study treatment and are clinically asymptomatic
Patients with known symptomatic brain metastases requiring steroids. Patients with previously diagnosed brain metastases are eligible if they are asymptomatic or have completed their treatment and have recovered from the acute effects of radiation therapy or surgery prior to the start of study medication, have discontinued corticosteroid treatment for these metastases for at least  weeks and are neurologically stable
Patients with untreated symptomatic brain metastases; patients with treated brain metastases will be allowed if brain imaging obtained greater than  days from trial enrollment reveals stable disease; patients with small (<  mm) asymptomatic brain metastasis are allowed to enroll; patients on steroids doses higher than  mg of prednisone (or its equivalent) are excluded
Participants with symptomatic brain metastases will be excluded from this clinical trial; subjects with asymptomatic, stable brain metastases and subjects who, if they have been previously treated for these conditions that are asymptomatic in the absence of corticosteroid therapy are allowed to enroll; brain metastasis must be stable with verification by imaging (brain magnetic resonance imaging [MRI] completed at screening demonstrating no current evidence of progressive brain metastases); if asymptomatic brain metastasis are first identified on the required pre-study scans, another set of scans must be completed to confirm that they are stable
Presence of brain metastases (unless they have been adequately treated with radiotherapy or surgery and stable for at least  days prior to enrollment provided patient is neurologically asymptomatic and without corticosteroid treatment for at least  days prior to enrollment)
Previously treated (surgery and/or radiation therapy) or untreated brain metastases are eligible, provided that patients are asymptomatic and not requiring escalating doses of corticosteroids
Patients with treated, stable, and asymptomatic brain metastases are eligible
Symptomatic brain metastases or leptomeningeal (LM) disease requiring corticosteroids for symptom management; asymptomatic brain metastases or LM will be allowed on study
Patients with uncontrolled brain metastases; patients with brain metastases must be asymptomatic and off corticosteroids for at least one week
Patients with active brain metastases; a scan to confirm the absence of brain metastases is not required for asymptomatic patients
Symptomatic or unstable brain metastases; (Note: asymptomatic patients with metastatic brain disease who have been on a stable dose of corticosteroid for treatment of brain metastases for at least  days [or decreasing dose of corticosteroid] are eligible to participate in the study); patients with primary central nervous system tumors are eligible
Brain metastases unless asymptomatic, stable and not requiring steroids for at least  weeks
Previously treated brain metastases (surgery and/or radiation therapy) are eligible, provided that patients are asymptomatic and not requiring corticosteroids
Patients with symptomatic uncontrolled brain metastases are excluded; (patients with stable treated or asymptomatic untreated brain metastasis not requiring glucocorticoids are allowed)
Subjects with untreated or uncontrolled brain metastases or evidence of leptomeningeal disease; patients with asymptomatic brain metastases or previously treated brain metastases that are stable (i.e. not requiring corticosteroids) at the time of study start will be eligible
Symptomatic or unstable brain metastases; (Note: asymptomatic patients with metastatic brain disease who have been on a stable dose of corticosteroids for treatment of brain metastases for at least  days prior to registration are eligible to participate in the study)
The patient has symptomatic brain metastases; asymptomatic brain metastases are permitted provided that there is no steroid requirement, no more than  metastases detected on standard MRI imaging, no metastatic brain lesion that is >  cm in size, and no lepto-meningeal disease
REGORAFENIB EXCLUSION CRITERIA: Known symptomatic brain metastases leptomeningeal involvement on unstable/increasing doses of steroid\r\n* Patients with asymptomatic brain metastases or leptomeningeal carcinomatosis may be enrolled at the discretion of the Sponsor as long as the patient is in clinically stable condition and, if requiring steroid, must be on a stable or decreasing dose for at least  days prior to regorafenib administration
Known or suspected untreated brain metastases; patients with radiographically stable, asymptomatic previously irradiated lesions are eligible provided patient is >= weeks beyond completion of cranial irradiation and >=  weeks off of corticosteroid therapy at the time of study intervention
Subject has known active central nervous system (CNS) involvement; the subject has untreated brain or meningeal metastases; computed tomography (CT) scans are not required to rule out brain or meningeal metastases unless there is a clinical suspicion of central nervous system disease; subjects with treated brain metastases that are radiographically or clinically stable for at least  weeks after therapy and have no evidence of cavitation or hemorrhage in the brain lesion(s) are eligible, providing that they are asymptomatic, and do not require corticosteroids (must have discontinued steroids at least  week prior to study drug administration)
Meningeal metastases or brain metastases that are symptomatic or untreated\r\n* Note: patients who are asymptomatic and have had post-treatment imaging that indicates stable brain disease are eligible; (patients with meningeal metastasis are not eligible even if stable following treatment); also, note that brain imaging is required within  weeks prior to initiation of study therapy
Patients with uncontrolled brain metastases; patients with brain metastases must be asymptomatic and off corticosteroids for at least one week
Symptomatic brain metastases; patients with known brain metastases are eligible if the metastases are asymptomatic and previously treated
Symptomatic brain metastases; patients with known brain metastases are allowed if they are asymptomatic
Previously treated patients with non-squamous NSCLC who have had brain metastases at any point in their treatment history are eligible for enrollment on this clinical trial; (patients must have received at least one regimen for systemic disease which may be cytotoxic or oral tyrosine kinase inhibitor therapy)\r\n* Patients with clinically asymptomatic (no requirement for systemic corticosteroids) untreated brain metastases will be allowed on trial at the discretion of the treating physician\r\n* Patients who have undergone treatment for their brain metastases with whole brain radiotherapy, stereotactic radiosurgery, or surgical resection must be clinically stable and recovered from all procedures at the time of study enrollment
Patients with locally treated, stable, and/or asymptomatic brain metastases are eligible
Symptomatic brain metastases (baseline CT scan is not required in asymptomatic patients)
Has CNS Disease: Participants with brain or subdural metastases are not eligible unless the metastases are asymptomatic and do not require treatment or have been adequately treated by local therapy (eg, surgery or radiotherapy) and have discontinued the use of corticosteroids for this indication for at least  weeks prior to study drug administration. Confirmation of radiographic stability must be done by comparing the brain scan (CT or MRI) performed during the Screening Period, using the same imaging modality, to a brain scan performed earlier (and following local therapy where applicable). Participants must be clinically stable. It is not the intention of this protocol to treat participants with active brain metastases. Note: CNS imaging is required to confirm eligibility for participants with a known history of CNS disease.
Symptomatic brain metastases; asymptomatic brain metastases are allowed provided that they have been treated, have been stable for greater than (>)  weeks as documented by radiographic imaging, and do not require prolonged (> days) systemic corticosteroid therapy
Patients with asymptomatic brain metastases that have been treated are eligible if the following criteria are met: No history of seizures in the preceding  months. Definitive treatment must have been completed >/=  weeks prior to registration. Subjects must be off steroids that were being administered because of brain metastases or related symptoms for >/=  weeks. Post-treatment imaging within  weeks of registration must demonstrate stability or regression of the brain metastases.
Patients with untreated, symptomatic brain metastases should be excluded from this clinical trial (patients with asymptomatic brain metastases amenable to treatment with Gamma Knife radiosurgery [GKRS] are eligible and may receive GKRS while on protocol)
Patients with a history of resected brain metastases are eligible only if they are asymptomatic and have stable MRI scans for  consecutive months, including =<  days of study registration
Subjects with known symptomatic brain metastasis are not suitable for enrolment. Subjects with asymptomatic, stable, treated brain metastases are eligible for study entry.
Patients with treated, stable, and asymptomatic brain metastases are eligible
Stage  solid tumor and stage  endometrial and ovarian cancer participants with known central nervous system (CNS) metastatic lesions which are symptomatic and/or growing; patients previously treated for these conditions that are asymptomatic in the absence of corticosteroid therapy are allowed to enroll; brain metastasis must be stable for  month with verification by imaging (brain MRI completed at screening demonstrating no current evidence of progressive brain metastases); CNS imaging will not be mandated for asymptomatic patients with no history of CNS metastases
Patients must have a CT or MRI scan of the brain to evaluate for central nervous system (CNS) disease within  days prior to registration; patient must not have symptomatic brain metastases or evidence of leptomeningeal carcinomatosis; patients with asymptomatic brain metastases are eligible if off of steroids for at least  days prior to registration without development of symptoms
Histologically confirmed malignant melanoma with measurable metastases in the brain. Both asymptomatic and symptomatic patients.
Patients with known active brain or central nervous system metastases, including leptomeningeal disease; patients with treated and asymptomatic brain metastases may be eligible after discussion with PI
Patients with untreated brain metastases are allowed provided that the patient is clinically asymptomatic and stable; patients with a prior history of symptomatic brain metastases are eligible provided:\r\n* The brain metastases have been treated\r\n* The patient is asymptomatic from the brain metastases at enrollment\r\n* Corticosteroids prescribed for the management of brain metastases have been discontinued at least  days prior to registration\r\n* The brain metastases are stable on pre-registration imaging
Patients with uncontrolled brain metastases; patients with brain metastasis must be asymptomatic and off corticosteroid use for at least one week
Participants with known leptomeningeal metastases or untreated brain metastases. Participants with known brain metastases will be eligible if they have completed the primary brain therapy (such as whole brain radiotherapy, stereotactic radiosurgery, or complete surgical resection) and if they have remained clinically stable, asymptomatic, and off steroids for at least  days.
Symptomatic central nervous system metastases; subjects with brain metastases that have been previously treated with whole body radiation therapy (WBXRT) and are stable for  weeks are allowed; (gamma or cyber knife treated lesions may enroll  weeks after completion if toxicities are resolved and no longer requiring steroids, patients with asymptomatic brain metastases are allowed after discussion with the study sponsor)
INCLUSION CRITERIA:\n\n          -  Age ?  years\n\n          -  Histologically confirmed diagnosis of unresectable stage III or metastatic melanoma\n             (stage IIIC to IV per American Joint Committee on Cancer [AJCC])\n\n          -  Documented evidence of BRAF V mutation.\n\n          -  Newly obtained tumor biopsy at baseline, and patient agrees to a mandatory biopsy at\n             the time of progression, if not medically contraindicated.\n\n          -  Evidence of measurable disease, as determined by RECIST v..\n\n        INCLUSION CRITERIA for triple combinations:\n\n        Progressive disease following prior treatment with LGX/MEK combination. PRINCIPAL\n        EXCLUSION CRITERIA Symptomatic or untreated leptomeningeal disease.\n\n          -  Symptomatic brain metastases. Patients previously treated or untreated for brain\n             metastases that are asymptomatic in the absence of corticosteroid therapy or on a\n             stable dose of steroids for four weeks are allowed to enroll. Brain metastases must be\n             stable at least  weeks with verification by imaging (e.g. brain MRI completed at\n             screening demonstrating no current evidence of progressive brain metastases). Patients\n             are not permitted to receive enzyme inducing anti-epileptic drugs.\n\n          -  Patients who have developed brain metastases during Part I of the study may continue\n             to Part II upon discussion with Novartis Medical Monitor. The brain metastasis must be\n             either asymptomatic or treated and stable for at least  weeks and on a stable or\n             tapering dose of steroids for at least  weeks. Patients with brain metastasis are not\n             eligible for the combination with LEE.\n\n          -  Known acute or chronic pancreatitis.\n\n          -  History or current evidence of retinal vein occlusion (RVO) or current risk factors\n             for RVO (e.g. uncontrolled glaucoma or ocular hypertension, history of hyperviscosity\n             or hypercoagulability syndromes);\n\n          -  Clinically significant cardiac disease including any of the following:\n\n          -  CHF requiring treatment (NYH grade ? ),\n\n          -  LVEF < % as determined by MUGA scan or ECHO\n\n          -  History or presence of clinically significant ventricular arrhythmias or atrial\n             fibrillation\n\n          -  Clinically significant resting bradycardia\n\n          -  Unstable angina pectoris ?  months prior to starting study drug\n\n          -  Acute Myocardial Infarction (AMI) ?  months prior to starting study drug,\n\n          -  QTcF >  msec. Patients with any of the following laboratory values at\n\n        Screening/baseline:\n\n          -  Absolute neutrophil count (ANC) <,/mm [. x /L]\n\n          -  Platelets < ,/mm [ x /L]\n\n          -  Hemoglobin < . g/dL\n\n          -  Serum creatinine >. x ULN or calculated or directly measured CrCl < % LLN (lower\n             limit of normal)\n\n          -  Serum total bilirubin >. x ULN\n\n          -  AST/SGOT or ALT/SGPT > . x ULN, or >  x ULN if liver metastases are present\n\n        Additional exclusion criteria for the triple combinations:\n\n        LGX/MEK/BKM:\n\n          -  Patients with fasting glucose >  mg/dL or . mmol/L, and HbAc >  %.\n\n          -  Patient has any of the following mood disorders as judged by the\n\n        Investigator or a Psychiatrist:\n\n          -  Patient has a score ?  on the PHQ- questionnaire\n\n          -  Patient has ? CTCAE grade  anxiety\n\n        LGX/MEK/BGJ:\n\n          -  History and/or current evidence of significant ectopic mineralization/ calcification\n             with the exception of calcified lymph nodes and asymptomatic vascular calcification.\n\n          -  Current evidence of corneal disorder/ keratopathy incl. but not limited to bullous/\n             band keratopathy, corneal abrasion, inflammation/ulceration, keratoconjunctivits etc.,\n             confirmed by ophthalmologic examination\n\n        LGX/MEK/LEE:\n\n          -  Patients with uncontrolled hypertension (please refer to WHO-ISHguidelines) are\n             excluded from study.\n\n          -  QTcF > ms for males and > ms for females Congenital long QT syndrome or family\n             history of unexpected sudden cardiac death and/or hypokalemia CTCAE Grade ?  and\n             magnesium levels below the clinically relevant lower limits at study entry\n\n          -  Current evidence of brain metastasis or brain metastasis detected by mandatory CT/MRI\n             at screening\n\n          -  PT/INR or aPTT > .xULN\n\n        Other protocol-defined inclusion/exclusion criteria may apply.
Active brain metastases: evidence of progression =<  months after local therapy (patients should be asymptomatic and off corticosteroids and anticonvulsants for at least  months prior to study entry)
Prior brain or leptomeningeal metastases allowed if asymptomatic (e.g., diagnosed incidentally at study baseline)
Have active brain metastases. Subjects with brain metastases are allowed if they completed definitive brain therapy, are asymptomatic and radiologically stable, and if they are not currently receiving corticosteroids or radiation.
Patient with stable or treated brain metastases are eligible; asymptomatic patients with metastatic brain disease who have been on a stable dose of corticosteroids for treatment of brain metastases for at least  days are eligible to participate in the study
Patients with known brain metastases are NOT eligible for participation unless the brain metastases are treated (either with surgical excision, stereotactic radiosurgery or radiotherapy) and have been stable based on the physicians assessment, the patient is asymptomatic and has discontinued corticosteroids if taken for that purpose
Symptomatic brain metastases; known brain metastases are allowed if asymptomatic and previously treated
At the time of day  of the study, subjects with brain metastases must be asymptomatic for at least  weeks and:
Participants with metastases are excluded if their brain metastases are:\r\n* Symptomatic\r\n* Treated (e.g., surgery, radiation therapy) but not clinically and radiographically stable one month after therapy (as assessed by at least two distinct contrast enhanced MRI or CT scans over at least a one month period), OR\r\n* Asymptomatic and untreated but >  cm in the longest dimension
All patients must undergo a CT or MRI of the brain within  days prior to registration; patients with asymptomatic brain metastases or previously treated brain metastases that are stable (i.e. not requiring corticosteroids) at the time of registration will be eligible
Participants with known and untreated brain metastases are excluded; note: patients without known prior central nervous system (CNS) metastases and without clinical signs and symptoms of CNS involvement are not required to have a magnetic resonance imaging (MRI) of the brain prior to enrollment; patients with treated brain metastases that are asymptomatic and clinically stable for two weeks will be eligible for protocol participation
Asymptomatic patients
Previously treated NSCLC with asymptomatic brain metastases (eligible for Arm M) See additional details below
Active brain metastases with the exception of subject has been treated and are asymptomatic and there has been no evidence of CNS progression for at least  weeks of first dose of MEDI-
Patients with untreated symptomatic brain metastases will be excluded from this study; those with treated brain metastases or untreated but asymptomatic sub-centimeter brain metastases will be allowed as long as they are neurologically asymptomatic and off steroids
Patients with untreated symptomatic brain metastases; patients with treated brain metastases will be allowed if brain imaging obtained within  days of trial enrollment reveals stable disease; patients with small asymptomatic brain metastasis are allowed to enroll; patients on steroids doses higher than  mg of prednisone (or its equivalent) are excluded
Symptomatic brain metastases (patients with asymptomatic brain metastases may be eligible provided other criteria are met)
Patients with brain metastases are eligible if asymptomatic and neurologically stable for at least  weeks and are not taking any medications contraindicated
At the time of day  of the study, patients with brain metastases must be asymptomatic and: ) at least  weeks without tumor progression after any whole brain radiotherapy, ) at least  weeks since craniotomy and resection or stereotactic radiosurgery, ) at least  weeks without new brain metastases as evidenced by MRI
Patients must have a CT or MRI scan of the brain to evaluate for CNS disease within  days prior to registration; patient must not have brain metastases unless: () metastases have been treated and have remained controlled for at least  days following treatment or was not treated, but is asymptomatic, AND () patient has no residual neurological dysfunction off corticosteroids or anti-convulsants for at least  days
Subjects with brain metastases are excluded if their brain metastases are: Symptomatic; Treated (surgery, radiation therapy) but not clinically and radiographically stable one month after local therapy, OR; Asymptomatic and untreated but >  cm in the longest dimension. Subjects with small (<=  cm in the longest dimension), asymptomatic brain metastases that do not need immediate local therapy can be enrolled. Subjects on a stable dose of corticosteroids for more than one month, or those who have been off corticosteroids for at least  weeks can be enrolled. Subjects must also be off of enzyme-inducing anticonvulsants for more than  weeks.
Brain metastases are allowed if the patient is asymptomatic or previous steroid treatment was discontinued >=  weeks
Subject must not have known untreated brain or meningeal metastases. CT scans are not required to rule out brain or meningeal metastases unless there is a clinical suspicion of central nervous system disease. Subjects with treated brain metastases that are radiographically or clinically stable for at least  weeks after therapy and have no evidence of cavitation or hemorrhage in the brain lesion(s) are eligible, provided that they are asymptomatic and do not require corticosteroids (must have discontinued steroids at least one week prior to study drug administration).
Patients with brain or leptomeningeal metastases are allowed on study if the lesions are asymptomatic without neurological signs and clinically stable for at least  weeks
Symptomatic, untreated or unstable central nervous system or leptomeningeal metastases; (patients with treated and stable brain metastases [confirmed by  scans at least  weeks apart], with no evidence of cavitation or hemorrhage in the brain lesion are eligible provided that they are asymptomatic and do not require corticosteroids)
Patient has evidence of clinically unstable brain metastases (controlled and stable brain metastasis must be previously treated and asymptomatic)
Brain metastases unless asymptomatic and not requiring steroids for at least  weeks prior to start of study treatment (Patients with SCLC or LCNEC of lung only must have CT or MRI of brain during screening, and if metastases found, must have radiotherapy with  day washout or stereotactic radiotherapy or radio surgery with  day washout)
Asymptomatic women
Brain metastases allowed if asymptomatic, without edema, and not receiving corticosteroids or radiation
Brain metastases allowed if asymptomatic at study baseline. Patients with untreated brain metastases must not be on corticosteroids. If patients have neurological symptoms or signs due to CNS metastases, patients need to complete whole brain radiation or focal treatment at least  days before start of study treatment and be asymptomatic on stable or decreasing doses of corticosteroids at baseline.