Advanced Non-Clear Cell Kidney Cancer Clinical Trial
Official title:
Phase II Study of Atezolizumab + Bevacizumab in Patients With Advanced Non-Clear Cell Renal Cell Carcinoma
| Verified date | May 2024 |
| Source | Dana-Farber Cancer Institute |
| Contact | n/a |
| Is FDA regulated | No |
| Health authority | |
| Study type | Interventional |
This research study is studying the combination of Atezolizumab and Bevacizumab as a possible treatment for Advanced Non-Clear Cell Kidney Cancer.
| Status | Active, not recruiting |
| Enrollment | 65 |
| Est. completion date | October 2024 |
| Est. primary completion date | November 13, 2019 |
| Accepts healthy volunteers | No |
| Gender | All |
| Age group | 18 Years and older |
| Eligibility | Inclusion Criteria: - Age = 18 years. - Unresectable advanced or metastatic non-clear cell RCC to include but not limited to: - Papillary RCC, any type - Unclassified RCC - Translocation RCC - Chromophobe RCC - Collecting duct RCC - Medulary RCC - Clear cell RCC or any histology with > 20% sarcomatoid features will be eligible. - Other non-clear cell histologies that are not included above need to be discussed with the PI. - Request for formalin-fixed, paraffin-embedded (FFPE) archival tumor specimens if available and willingness of the participant to undergo mandatory fresh tumor biopsy unless determined medically unsafe or not feasible. A note from the study team should be provided documenting availability of tissue. If a target lesion is biopsied at screening, this lesion must be followed as non-target lesion after the biopsy unless it is the patient's only target lesion. If there is only one target lesion, it should be followed as a target lesion regardless. - The archival specimen should contain adequate viable tumor tissue. - The specimen may consist of a tissue block (preferred and should contain the highest grade of tumor) or at least 30 unstained serial sections. Fine-needle aspiration, brushings, cell pellet from pleural effusion, bone marrow aspirate/biopsy are not acceptable. - Fresh tumor biopsy at progression will be required in cases where patients experience relapse after an initial response if medically safe. - Measurable disease as defined by Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1. - ECOG performance status = 2 (See Appendix A). - Adequate hematologic and end-organ function as defined by the following laboratory results obtained within 28 days prior to the first study treatment: - Absolute neutrophil count (ANC) = 1500 cells/uL. - Lymphocyte count = 500/uL. - Platelet count = 100,000/uL. - Hemoglobin = 9 g/dL (patients may be transfused to meet this criterion). - Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) = 2.5 x upper limit of normal (ULN) with the following exceptions: Patients with documented liver metastases should have AST and ALT = 5 x ULN. - Serum bilirubin = 2.0 x ULN with the following exception: Patients with known Gilbert's disease should have a serum bilirubin = 3 x ULN. - Creatinine clearance = 30 mL/min as calculated by Cockcroft-Gault equation. - For female patients of childbearing potential and male patients with partners of childbearing potential, agreement (by patient and/or partner) to use highly effective forms of contraception and to continue its use 6 months after the last dose of atezolizumab or bevacizumab. - Signed informed consent form. - Ability and capacity to comply with study and follow-up procedures. Exclusion Criteria •Prior treatment with CD137 agonists, anti- cytotoxic T-lymphocyte-associated protein 4, anti-PD-1, or anti-PDL1 therapeutic antibody or pathway targeting agents. Prior IFNa or IL-2 is allowed following 4 week washout from treatment end date. - Receipt of any type of small molecule kinase inhibitor (including investigational kinase inhibitors) within 2 weeks of enrollment or receipt of any anti-cancer therapy (including investigational therapy, monoclonal antibodies, cytokine therapy) within 4 weeks of enrollment. - Prior therapy with bevacizuamab. - Thrombologic event within 3 weeks of treatment start date, unless stable on anticoagulation with LMWH or Factor Xa inhibitor for at least 2 weeks. - Treatment with systemic immunosuppressive medications including but not limited to: prednisone, dexamethasone, cyclosporin, azathioprine, methotrexate, thalidomide, anti- tumor necrosis factor (TNF) agents, hydroxychloroquine within 2 weeks of first study dose. - Patients who have received acute, low-dose systemic immunosuppressant medications may be enrolled. - Patients with adrenal insufficiency on physiologic replacement doses of steroids may be enrolled. - The use of inhaled, topical intraocular, or intra articular corticosteroids or, mineralocorticoids are allowed. - Radiotherapy for RCC within 14 days of first study treatment with the exception of a single fraction of radiation administered for palliation of symptoms. - Known brain metastases or cranial epidural disease unless adequately treated with radiotherapy, radiosurgery, or surgery and stable for at least 4 weeks prior to the initiation of study treatment. Stability must be confirmed by magnetic resonance imaging (MRI) or computed tomography (CT) imaging and/or treating investigator determination. - Malignancies other than RCC within 2 years of first study treatment with the exception of those with negligible risk of metastases or death (included but not limited to carcinoma in situ of the cervix, basal or squamous cell skin cancer, localized prostate cancer, ductal carcinoma in situ of the breast, non-muscle invasive urothelial carcinoma, or other malignancy not deemed to impact that patients 5-year life expectancy). - History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion protein. - Known hypersensitivity to any component of the atezolizumab product. - History of autoimmune disease including: myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with anti-phospholipid syndrome, Wegner's granulomatosis, Sjogren's syndrome, Guillain-Barre syndrome, multiple sclerosis, type I diabetes mellitus, vasculitis, or glomerulonephritis. Patients with a history of autoimmune-related hypothyroidism on thyroid replacement hormone or those with autoimmune dermatologic conditions not requiring the use of prednisone > 10 mg or equivalent are eligible. - History of idiopathic pulmonary fibrosis, organized pneumonia, drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis on screening imaging CT of the chest. History of radiation pneumonitis in the radiation field is permitted. - Positive test for HIV (test to be performed within 28 days of first treatment start). - Patients with active or chronic hepatitis B (defined as having a positive hepatitis B surface antigen [HBsAg] test at screening). Patients with past/resolved HBV infection (defined as having negative HBsAg test and a positive antibody to hepatitis B core antigen [anti-HBc] antibody test) are eligible. A negative HBA DNA test must be obtained in patients with positive hepatitis B core antibody prior to Cycle 1 Day 1. - Active hepatitis C infection. Patients positive hepatitis C antibody test are eligible if PCR is negative for hepatitis C viral DNA. - Infection requiring receipt of therapeutic oral or IV anti-microbials within 2 weeks of first study treatment. Patients receiving routine anti-microbial prophylaxis (for dental extractions/procedures) are eligible. - Significant cardiovascular disease such as New York Heart Association (NYHA) class II or greater, myocardial infarction within the previous 3 months of first study treatment, unstable arrhythmias, unstable angina. Patients with known coronary artery disease, congestive heart failure not meeting the above criteria, or left ventricular ejection fraction < 50% must be on a stable regimen that is optimized in the opinion of the treating physician, in consultation with a cardiologist when appropriate. - Inadequately controlled hypertension (defined as systolic blood pressure > 150 mmHg and/or diastolic blood pressure > 100 mmHg). Anti-hypertensive therapy to achieve these parameters is allowed. - Prior history of hypertensive crisis or hypertensive encephalopathy within the previous 3 months of first study treatment. - History of stroke or transient ischemic attack within 3 months of first study dose. - Significant vascular disease (such as aortic aneurysm requiring surgical repair or recent peripheral arterial thrombosis) within 6 months of first study dose. Evidence of bleeding diathesis or significant coagulopathy (in the absence of therapeutic anticoagulation). - Current or recent use of dipyramidole, ticlopidine, clopidogrel, cilostazol is excluded. Aspirin (= 325 mg per day) is allowed. Prophylactic anticoagulation with oral or parenteral anticoagulants for the patency of venous access devices or other indications is allowed. Therapeutic use of low-molecular weight heparin (such as enoxaparin), and factor Xa inhibitors are allowed. Use of warfarin is prohibited. - Use of plaquenil must be discontinued two weeks prior to first study treatment. - History of abdominal or tracheoesophageal fistula or GI perforation within 6 months of first study treatment. - Clinical signs or symptoms of active GI obstruction or requirement of routine parenteral nutrition or tube feedings. - Evidence of abdominal free air not explained by paracentesis or recent surgical procedure. - Serious, non-healing or dehiscing wound or active ulcer. - Proteinuria, as demonstrated by > 1.5 gram of protein in a 24-hour urine collection. All patients with = 2+ protein on dipstick urinalysis at baseline must undergo 24-hour urine collection for protein. - Major surgical procedure within 21 days of first study treatment. - Prior allogenic stem cell or solid organ transplant. - Administration of a live, attenuated vaccine within 4 weeks for first study treatment. - Pregnant or lactating women. |
| Country | Name | City | State |
|---|---|---|---|
| United States | Beth Israel Deaconess Medical Center | Boston | Massachusetts |
| United States | Dana Farber Cancer Institute | Boston | Massachusetts |
| United States | Karmanos Cancer Institute | Detroit | Michigan |
| United States | University of California, San Diego Moores Cancer Center | La Jolla | California |
| Lead Sponsor | Collaborator |
|---|---|
| Dana-Farber Cancer Institute | Genentech, Inc. |
United States,
McGregor BA, McKay RR, Braun DA, Werner L, Gray K, Flaifel A, Signoretti S, Hirsch MS, Steinharter JA, Bakouny Z, Flippot R, Wei XX, Choudhury A, Kilbridge K, Freeman GJ, Van Allen EM, Harshman LC, McDermott DF, Vaishampayan U, Choueiri TK. Results of a M — View Citation
Saliby RM, El Zarif T, Bakouny Z, Shah V, Xie W, Flippot R, Denize T, Kane MH, Madsen KN, Ficial M, Hirsch L, Wei XX, Steinharter JA, Harshman LC, Vaishampayan UN, Severgnini M, McDermott DF, Lee GM, Xu W, Van Allen EM, McGregor BA, Signoretti S, Choueiri TK, McKay RR, Braun DA. Circulating and Intratumoral Immune Determinants of Response to Atezolizumab plus Bevacizumab in Patients with Variant Histology or Sarcomatoid Renal Cell Carcinoma. Cancer Immunol Res. 2023 Aug 3;11(8):1114-1124. doi: 10.1158/2326-6066.CIR-22-0996. — View Citation
| Type | Measure | Description | Time frame | Safety issue |
|---|---|---|---|---|
| Primary | Best Overall Response Rate | The best overall response rate is the percentage of participants achieving complete response (CR) or partial response (PR) as the best response recorded on treatment based on Response Evaluation Criteria In Solid Tumors Criteria (RECIST 1.1) criteria.
CR and PR must meet the following lesion criteria without having any new lesions as well: Target Lesion: (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. Non-Target Lesion: (CR): Disappearance of all non-target lesions and normalization of tumor marker level. All lymph nodes must be non-pathological in size (<10 mm short axis). Non-CR/Non-Progressive Disease: Persistence of one or more non-target lesion(s) and/or maintenance of tumor marker level above the normal limits. Must have PR in target lesion. |
Measured every 6 weeks for the first 24 weeks and then every 12 weeks while on treatment. The median (range) of treatment time was 9.5 (1-42) cycles, thus participants were assessed up to ~32 months . | |
| Secondary | Best Overall Response Rate by Histological Subtypes | The best overall response rate is the percentage of participants achieving complete response (CR) or partial response (PR) as the best response recorded on treatment based on Response Evaluation Criteria In Solid Tumors Criteria (RECIST 1.1) criteria. Please see the primary endpoint "Best Overall Response Rate" description for the definition of CR and PR.
Non-clear cell renal cell carcinoma includes different histologic and genetic subtypes to include: papillary, chromophobe, collecting duct, unclassified, translocation, and medullary carcinoma. These subtypes are measured using established methods. |
Measured every 6 weeks for the first 24 weeks and then every 12 weeks while on treatment. The median (range) of treatment time was 9.5 (1-42) cycles, thus participants were assessed up to ~32 months | |
| Secondary | Percentage of Participants With Treatment-related Adverse Events | Assessed by -Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. All treatment-related all-grade adverse events occurring in >10% of participants.
Treatment Related is discerned as follows: Yes: There is a plausible temporal relationship between the onset of the AE and administration of atezolizumab or bevacizumab, and the AE cannot be readily explained by the patient's clinical state, intercurrent illness, or concomitant therapies; and/or the AE follows a known pattern of response to atezolizumab or bevacizumab or with similar treatments; and/or the AE resolves upon discontinuation of the study drugs or dose reduction and, if applicable, reappears upon re-challenge. No: Evidence exists that the AE has an etiology other than the study drugs (e.g., pre existing medical condition, underlying disease, intercurrent illness, or concomitant medication); and/or the AE has no plausible temporal relationship to the study drugs administration. |
Adverse events are measured continuously on treatment and up to thirty days after going off treatment (up to ~32 months). | |
| Secondary | Duration of Response | The duration of overall response (based on RECIST 1.1) is measured from the time measurement criteria are met for CR and PR (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented taking as reference for progressive disease the smallest measurements recorded since the treatment started or death due to any cause. Participants without events reported are censored at the last disease evaluation. | Measured every 6 weeks for the first 24 weeks and then every 12 weeks while on treatment. Off-treatment, patients are followed every 6 months for up to two year. Participants were followed up to 32 months. | |
| Secondary | Immune Related Best Overall Response Rate | The best overall Immune-Related Complete Response (irCR) or Immune-Related Partial Response (irPR) is the best response recorded from the start of the treatment until disease progression/recurrence (taking as reference for progressive disease the smallest measurements recorded since the treatment started).
irCR: Complete disappearance of all target lesions in two consecutive observations not less than 4 weeks apart. This category encompasses exactly the same subjects as complete response (CR). irPR: Decrease, relative to baseline, of 50% or greater in the sum of the products of the two largest perpendicular diameters (SPD) of all target and all new measurable lesions in two consecutive observations not less than 4 weeks apart. Note: the appearance of new measurable lesions is factored into the overall tumor burden, but does not automatically qualify as progressive disease until the SPD increases by > 25% when compared to SPD at nadir. |
Measured every 6 weeks while on treatment. Off-treatment, patients are followed every 6 months for up to two year. Participants were followed up to 32 months. | |
| Secondary | Median Progression Free Survival | Progression free survival (PFS) is defined as the time from start of treatment to disease progression (PD) or death from any cause as estimated by Kaplan Meier methods. Patients who have not progressed and are alive are censored at the date the patient is known to be progression-free. Progression is defined by Response Evaluation Criteria In Solid Tumors Criteria 1.1 (RECIST) as follows:
- >20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (including baseline if it's the smallest). The sum must also demonstrate an increase of >5 mm. OR -Appearance of new lesions and/or unequivocal progression of non-target lesions. It must be representative of overall disease status change, not a single lesion increase. For patients with PD at the first on-treatment imaging assessment, patients will be allowed to remain on study until confirmation at the next assessment at investigator discretion if patient is benefiting from treatment. |
Participants followed for up to 32 months. | |
| Secondary | 1-Year Overall Survival | 1-Year Overall Survival (OS) is defined as the probability of survival at 1 year from treatment start date. Survival probability is estimated using Kaplan Meier methods. An event is considered to be death due to any cause. Participants who are lost to follow-up before the 1 year mark are censored at date last known alive. | 1 year | |
| Secondary | Mean Function Assessment of Cancer Therapy-Kidney Symptom Index-19 Score | The Function Assessment of Cancer Therapy-Kidney Symptom Index-19 (FKSI-19) is a 19 item questionnaire with each item scored on a scale of 0-4 for a total score of 0-76 with higher scores indicating fewer symptom. | Assessed at baseline, week 3, week 5, week 7, week 9, and end of therapy. | |
| Secondary | Brief Fatigue Inventory Score - Items 1-3 | The Brief Fatigue Inventory Score (BFI) is a 9 item questionnaire with each items 1-3 scored on a scale of 0-10 Scores are categorized is mild (1-3), moderate (4-6), or severe (7-10). A global fatigue score can be found by averaging the score obtained on each test item completed. Items 1-3 of the 9 are reported here. | Assessed at baseline, week 9, week 15, week 21, week 27, and end of therapy. | |
| Secondary | 6-Month Progression-Free Survival by Histological Subgroups | 6-Month Progression free survival (PFS) is defined as the probability of disease progression (PD) or death from any cause 6 months from treatment start date as estimated by Kaplan Meier methods. Patients who have not progressed and alive are censored at the date the patient is known to be progression-free. Progression is defined by RECIST 1.1 as follows:
- >20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study. The sum must also demonstrate an increase of >5 mm. OR -Appearance of new lesions and/or unequivocal progression of non-target lesions. It must be representative of overall disease status change, not a single lesion increase. For patients with PD at the first on-treatment imaging assessment, patients will be allowed to remain on study until confirmation at the next assessment at investigator discretion if patient is benefiting from treatment. Histological subgroups are categorized using established methods. |
6 months | |
| Secondary | 1-Year Overall Survival by Histological Subgroup | 1-Year Overall Survival (OS) is defined as the probability of survival at 1 year from treatment start date. Survival probability is estimated using Kaplan Meier methods. An event is considered to be death due to any cause. Participants who are lost to follow-up before the 1 year mark are censored at date last known alive. | 1 year | |
| Secondary | 6-Month Progression-Free Survival by Sarcomatoid Differentiation | 6-Month Progression free survival (PFS) is defined as the probability of disease progression (PD) or death from any cause 6 months from treatment start date as estimated by Kaplan Meier methods. Patients who have not progressed and alive are censored at the date the patient is known to be progression-free. Progression is defined by RECIST 1.1 as follows:
- >20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study. The sum must also demonstrate an increase of >5 mm. OR -Appearance of new lesions and/or unequivocal progression of non-target lesions. It must be representative of overall disease status change, not a single lesion increase. For patients with PD at the first on-treatment imaging assessment, patients will be allowed to remain on study until confirmation at the next assessment at investigator discretion if patient is benefiting from treatment. Sarcomatoid Differentiation are categorized using established methods |
6 months | |
| Secondary | 1-Year Overall Survival by Sarcomatoid Differentiation | 1-Year Overall Survival (OS) is defined as the probability of survival at 1 year from treatment start date. Survival probability is estimated using Kaplan Meier methods. An event is considered to be death due to any cause. Participants who are lost to follow-up before the 1 year mark are censored at date last known alive. | 1 year | |
| Secondary | Objective Response Rate by Sarcomatoid Differentiation | The objective response rate is the percentage of participants achieving complete response (CR) or partial response (PR) as the best response on treatment using Response Evaluation Criteria In Solid Tumors Criteria (RECIST 1.1).
CR and PR must meet the following criteria without having any new lesions as well: Target Lesion: (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. (PR): >=30% decrease in the sum of the diameters of target lesion, taking as reference the baseline sum diameter. Non-Target Lesion: (CR): Disappearance of all non-target lesions and normalization of tumor marker level. All lymph nodes must be non-pathological (<10 mm short axis) Non-CR/Non-Progressive Disease: Persistence of 1+ non-target lesion(s) and/or maintenance of tumor marker level above the normal limits. Must have PR in target lesion Sarcomatoid Differentiation are categorized using established methods |
Measured every 6 weeks for the first 24 weeks and then every 12 weeks while on treatment. The median (range) of treatment time was 9.5 (1-42) cycles, thus participants were assessed up to ~32 months . | |
| Secondary | 6-Month Progression-Free Survival by International Metastatic Renal Cell Carcinoma Risk Group | 6-Month Progression free survival (PFS) is defined as the probability of disease progression (PD) or death from any cause 6 months from treatment start date as estimated by Kaplan Meier methods. Patients who have not progressed and alive are censored at the date the patient is known to be progression-free. Progression is defined by RECIST 1.1 as follows:
- >20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum. The sum must also demonstrate an increase of >5 mm. OR -Appearance of new lesions and/or unequivocal progression of non-target lesions. It must be representative of overall disease status change, not a single lesion increase. For patients with PD at the first on-treatment imaging assessment, patients will be allowed to remain on study until confirmation at next assessment at investigator discretion if patient is benefiting from treatment. International Metastatic Renal Cell Carcinoma Risk Group determined by established methods |
6 months | |
| Secondary | 1-Year Overall Survival by International Metastatic Renal Cell Carcinoma Risk Group | 1-Year Overall Survival (OS) is defined as the probability of survival at 1 year from treatment start date. Survival probability is estimated using Kaplan Meier methods. An event is considered to be death due to any cause. Participants who are lost to follow-up before the 1 year mark are censored at date last known alive. | 1 year | |
| Secondary | Objective Response Rate by International Metastatic Renal Cell Carcinoma Risk Group | The objective response rate is the percentage of participants achieving complete response (CR) or partial response (PR) as the best response on treatment using RECIST 1.1.
CR and PR must meet the following criteria without having any new lesions as well: Target Lesion: (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. (PR): >=30% decrease in the sum of the diameters of target lesion, taking as reference the baseline sum diameter. Non-Target Lesion: (CR): Disappearance of all non-target lesions and normalization of tumor marker level. All lymph nodes must be non-pathological (<10 mm short axis). Non-CR/Non-Progressive Disease: Persistence of 1+ non-target lesion(s) and/or maintenance of tumor marker level above the normal limits. Must have PR in target lesion. International Metastatic Renal Cell Carcinoma Risk Group are categorized using established methods |
Measured every 6 weeks for the first 24 weeks and then every 12 weeks while on treatment. The median (range) of treatment time was 9.5 (1-42) cycles, thus participants were assessed up to ~32 months . | |
| Secondary | 6-Month Progression-Free Survival by Prior Systemic Therapy | 6-Month Progression free survival (PFS) is defined as the probability of disease progression (PD) or death from any cause 6 months from treatment start date as estimated by Kaplan Meier methods. Patients who have not progressed and alive are censored at the date the patient is known to be progression-free. Progression is defined by RECIST 1.1 as follows:
- >20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study. The sum must also demonstrate an increase of >5 mm. OR -Appearance of new lesions and/or unequivocal progression of non-target lesions. It must be representative of overall disease status change, not a single lesion increase. For patients with PD at the first on-treatment imaging assessment, patients will be allowed to remain on study until confirmation at the next assessment at investigator discretion if patient is benefiting from treatment. Prior systemic therapy group determined by established methods, |
6 months | |
| Secondary | 1-Year Overall Survival by Prior Systemic Therapy | 1-Year Overall Survival (OS) is defined as the probability of survival at 1 year from treatment start date. Survival probability is estimated using Kaplan Meier methods. An event is considered to be death due to any cause. Participants who are lost to follow-up before the 1 year mark are censored at date last known alive. | 1 year | |
| Secondary | Objective Response Rate by Prior Systemic Therapy | The objective response rate is the percentage of participants achieving complete response (CR) or partial response (PR) as the best response on treatment using RECIST 1.1.
CR and PR must meet the following criteria without having any new lesions as well: Target Lesion: (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. (PR): >=30% decrease in the sum of the diameters of target lesion, taking as reference the baseline sum diameter. Non-Target Lesion: (CR): Disappearance of all non-target lesions and normalization of tumor marker level. All lymph nodes must be non-pathological (<10 mm short axis). Non-CR/Non-Progressive Disease: Persistence of 1+ non-target lesion(s) and/or maintenance of tumor marker level above the normal limits. Must have PR in target lesion. |
Measured every 6 weeks for the first 24 weeks and then every 12 weeks while on treatment. The median (range) of treatment time was 9.5 (1-42) cycles, thus participants were assessed up to ~32 months . |