scholarly journals Protocol description of the HOVON 141/VISION trial: a prospective, multicentre, randomised phase II trial of ibrutinib plus venetoclax in patients with creatinine clearance ≥30 mL/min who have relapsed or refractory chronic lymphocytic leukaemia (RR-CLL) with or without TP53 aberrations

BMJ Open ◽  
2020 ◽  
Vol 10 (10) ◽  
pp. e039168
Author(s):  
Mark-David Levin ◽  
Arnon Kater ◽  
Mattias Mattsson ◽  
Sabina Kersting ◽  
Juha Ranti ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukaemia ◽  
Lymphocytic Leukaemia ◽  
Residual Disease ◽  
Medical Center ◽  
Progression Free Survival ◽  
Inclusion Criteria ◽  
Exclusion Criteria ◽  
Free Survival ◽  
Informed Consent Form ◽  
Registration Number

IntroductionLiterature is scarce on the combination treatment of ibrutinib and venetoclax (IV) is scarce in relapsed or refractory chronic lymphocytic leukaemia (RR-CLL). Especially, the possibility of stopping ibrutinib in RR-CLL patients in deep remission is unclear.Methods and analysisIn the HOVON 141/VISION trial, patients with RR-CLL are treated with 12 cycles of IV after a short induction with ibrutinib. Patients reaching undetectable minimal residual disease (uMRD) after 12 cycles of IV are randomised 1:2 to continue ibrutinib or stop treatment. The persistence of uMRD after stopping IV is studied. In addition, in patients who become positive for MRD again after stopping, IV treatment is reinitiated. The efficacy of this approach with regard to progression-free survival 12 months after randomisation is the primary endpoint of the study.Ethics and disseminationThis protocol respects the Helsinki declaration and has been approved by the ethical committee of the Amsterdam Medical Center. Study findings will be disseminated through peer-reviewed papers. All patients who fulfil the inclusion criteria and no-exclusion criteria, and have signed the informed consent form are included in the study.Trial registration numberClinicalTrials.gov Registry (NCT03226301).

High Dose Methylprednisolone and Rituximab Is an Effective Therapy in Advanced Refractory Chronic Lymphocytic Leukaemia Resistant to Fludarabine Therapy.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3125-3125
Author(s):  
Moez Dungarwalla ◽  
Pamala Kanagasabapathy ◽  
Samar Kulkarni ◽  
Steve O. Evans ◽  
Unell Riley ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukaemia ◽  
Viral Infections ◽  
Lymphocytic Leukaemia ◽  
Fungal Infections ◽  
Single Agent ◽  
Progression Free Survival ◽  
High Dose ◽  
Fish Analysis ◽  
Free Survival ◽  
High Dose Methylprednisolone

Abstract The management of refractory advanced chronic lymphocytic leukaemia (CLL) continues to pose a considerable challenge to the clinician. CLL patients who are refractory or become resistant to fludarabine containing regimens currently have a poor prognosis. High dose methylprednisolone (HDMP) has been shown to be an effective therapeutic option in patients who are resistant to fludarabine particularly those with bulky lymphadenopathy or refractory cytopenias who are unsuitable for alemtuzumab therapy. We have used HDMP in combination with the anti-CD20 monoclonal antibody, Rituximab, to treat 14 patients with advanced refractory CLL. Eight of fourteen patients were male. The median age was 62.5 years (range 30–71). Twelve patients had bulky lymphadenopathy with nodal masses greater than 5 centimetres in diameter. Nine patients had Binet stage C and the remainder were stage B. Autoimmune manifestations were present in five of the patients, and in one of them fludarabine therapy was contraindicated due to active autoimmune haemolysis. FISH analysis was performed to detect 17p, 11q and 13q deletions and showed 11q23 deletions in five patients. The overall response rate was 93% with a median progression free survival (PFS) of seven months. Two patients achieved a CR, another a nodular PR and 10 patients had a PR. Responses were seen in all 4 patients who had not responded to alemtuzumab as a single agent. Only one patient failed to respond. The median survival was 20 months. All five patients with 11q23 deletions responded, and the mean progression free survival in this subgroup was 10.5 months. These results compare extremely favourably with our own previous study (Thornton et al, 1998) that used HDMP alone in the management of advanced/refractory CLL where only 43% of patients responded and no patients achieved a CR. We have demonstrated that the combination of HDMP with rituximab is more effective than HDMP alone (p<0.01) in advanced refractory CLL. Although HDMP in combination with rituximab causes little or no myelosuppression, 6/14 patients (43%) developed opportunistic fungal or viral infections and this included fungal mould infections, fungal yeast infections and opportunistic viral infections. Three patients died of pulmonary fungal infections, although 2 of these patients had been retreated with alternative regimens. While the immunosuppressive effects of high dose steroids are well recognised, it appears that the addition of rituximab has made these patients more prone to opportunistic infections. In summary, HDMP in combination with rituximab is an effective rescue regime in purine analogue refractory CLL particularly in patients with bulky lymphadenopathy who are unsuitable for alemtuzumab, and in patients with 11q23 deletions.

Measurable Residual Disease Does Not Preclude Prolonged Progression-free Survival in CLL Treated with Ibrutinib

Blood ◽  
2021 ◽  
Author(s):  
Victoria Wang ◽  
Curtis A. Hanson ◽  
Renee Tschumper ◽  
Connie Lesnick ◽  
Esteban Braggio ◽  
...  
Keyword(s):  
Treatment Efficacy ◽  
Residual Disease ◽  
Progression Free Survival ◽  
Surrogate Endpoint ◽  
Phase 3 ◽  
Free Survival ◽  
Hazard Ratios ◽  
Additional Support ◽  
Over Time ◽  
Measurable Residual Disease

E1912 was a randomized phase 3 trial comparing indefinite ibrutinib plus six cycles of rituximab (IR) to six cycles of fludarabine, cyclophosphamide and rituximab (FCR) in untreated younger patients with CLL. We describe measurable residual disease (MRD) levels in E1912 over time and correlate them with clinical outcome. Undetectable MRD rates (&lt; 1 CLL cell per 104 leukocytes) were 29.1%, 30.3%, 23.4% and 8.6% at 3, 12, 24 and 36 months for FCR, and significantly lower at 7.9%, 4.2% and 3.7% at 12, 24 and 36 months for IR, respectively. Undetectable MRD at 3, 12, 24 and 36 months was associated with longer progression-free survival (PFS) for the FCR arm with hazard ratios (MRD detectable / MRD undetectable) of 4.29 (95% CI 1.89 - 9.71), 3.91 (95% CI 1.39 - 11.03), 14.12 (95% CI 1.78 - 111.73), and not estimable (no events among those with undetectable MRD), respectively. For the IR arm, patients with detectable MRD did not have significantly worse PFS compared to those in whom MRD was undetectable; however, PFS was longer for those with MRD levels of less than 10-1 compared to those with MRD levels above this threshold. Our observations provide additional support for the use of MRD as a surrogate endpoint for PFS in patients receiving FCR. For patients on indefinite ibrutinib-based therapy, PFS did not differ significantly by undetectable MRD status, while those with MRD less than 10-1 tend to have longer PFS, although continuation of ibrutinib is very likely required to maintain treatment efficacy.

scholarly journals Phase II trial of ribociclib and letrozole in patients with relapsed oestrogen receptor-positive ovarian or endometrial cancers

ESMO Open ◽  
2020 ◽  
Vol 5 (5) ◽  
pp. e000926
Author(s):  
Gerardo Colon-Otero ◽  
Valentina Zanfagnin ◽  
Xiaonan Hou ◽  
Nathan R Foster ◽  
Erik J Asmus ◽  
...  
Keyword(s):  
Phase Ii ◽  
Oestrogen Receptor ◽  
Progression Free Survival ◽  
Clinical Activity ◽  
Low Grade ◽  
Free Survival ◽  
Platinum Sensitive ◽  
Er Positive ◽  
Registration Number ◽  
Pdx Models

ObjectiveWe describe a phase II clinical trial of the combination of ribociclib and letrozole for treatment of relapsed oestrogen receptor (ER)-positive ovarian cancer (OC) and endometrial cancer (EC). The primary endpoint was the proportion of patients alive, progression-free survival (PFS), and still on treatment at 12 weeks (PFS12), with 45% or greater considered positive.MethodsPatients with measurable, relapsed ER-positive OC or EC (platinum-sensitive or resistant) were eligible and treated with 400 mg of oral ribociclib and 2.5 mg of oral letrozole daily. Patient-derived xenografts (PDXs) were created from imaging-guided tumour biopsies.ResultsForty patients (20 OC and 20 EC) were enrolled. A PFS12 of 55% was observed in the EC cohort and 50% in the OC cohort. A PFS greater or equal to 24 weeks (PFS24) was seen in 20% (4/20) of the OC cohort and 35% (7/20) of the EC cohort. The greatest benefit was seen in low-grade serous OC (LGSOC) (3/3, 100% PFS24) and grades 1 and 2 EC (5/11, 45% PFS24). All three LGSOC patients obtained at least a partial response lasting for over 2 years, with two of the three patients still on treatment. PDX tumour engraftment was feasible in 45% of patients. Positive survival effects of the combination of ribociclib and letrozole were observed in two of three EC PDX models.ConclusionRibociclib and letrozole have promising clinical activity in relapsed ER-positive OC and EC, particularly in LGSOC and relapsed ER-positive grade 1 and 2 EC. Generation of PDX models is feasible with positive survival effects observed in EC models.Trial registration numberClinicalTrials.gov registry (NCT02657928).

A randomized trial comparing cisplatin plus cyclophosphamide versus cisplatin, doxorubicin, and cyclophosphamide in advanced ovarian cancer.

1986 ◽  
Vol 4 (6) ◽  
pp. 965-971 ◽  
Author(s):  
P F Conte ◽  
M Bruzzone ◽  
S Chiara ◽  
M R Sertoli ◽  
M G Daga ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Median Survival ◽  
Stable Disease ◽  
Residual Disease ◽  
Performance Status ◽  
Advanced Ovarian Cancer ◽  
Progression Free Survival ◽  
Complete Response ◽  
Free Survival ◽  
Second Look

After primary surgery, 125 patients with epithelial ovarian cancer (International Federation of Gynaecology and Obstetrics [FIGO] 1c + IIb + IIc = 22 patients, FIGO III = 82 patients, FIGO IV = 21 patients) were randomly allocated to receive PC (cisplatin 50 mg/m2 + cyclophosphamide 600 mg/m2 on day 1 every 28 days) (corrected) or PAC (PC + doxorubicin 45 mg/m2). After six cycles, patients clinically disease-free or with resectable residual disease were submitted to second-look surgery. After restaging, patients in surgical complete response (CR) stopped treatment while those responding partially (PR) received six more courses; patients whose disease progressed were excluded from the study. Among patients with measurable disease, the following clinical response rates were observed: PC = 20% CR, 34.3% PR, 14.3% stable disease, and 31.4% progression; PAC = 40.6% CR, 15.6% PR, 12.5% stable disease, and 31.3% progression. In the 75 patients submitted to second look, the results have been the following: PC = 39.5% CR, 36.8% PR, 7.9% stable disease, and 15.8% progression; PAC = 62.2% CR, 18.9% PR, 10.8% stable disease, and 8.1% progression. The difference in surgical complete response in favor of the PAC regimen is significant (P less than .05). Median survival and progression-free survival were 800 and 400 days, respectively, for PAC arm; median survival and progression-free survival were 680 and 380 days, respectively, for PC. These differences are not significant. Probability of survival was affected by FIGO stage, amount of residual disease, histology, performance status, and response at second look, while no influence was observed according to grade of tumor differentiation and age. Our results demonstrate the usefulness of doxorubicin in terms of surgical CR.

scholarly journals Systematic Review of Intravenous Ascorbate in Cancer Clinical Trials

Antioxidants ◽  
2018 ◽  
Vol 7 (7) ◽  
pp. 89 ◽  
Author(s):  
Gina Nauman ◽  
Javaughn Gray ◽  
Rose Parkinson ◽  
Mark Levine ◽  
Channing Paller
Keyword(s):  
Vitamin C ◽  
Progression Free Survival ◽  
Clinical Effectiveness ◽  
Standard Of Care ◽  
Controlled Trials ◽  
Narrative Approach ◽  
Cancer Clinical Trials ◽  
Inclusion Criteria ◽  
Free Survival ◽  
To Receive

Background: Ascorbate (vitamin C) has been evaluated as a potential treatment for cancer as an independent agent and in combination with standard chemotherapies. This review assesses the evidence for safety and clinical effectiveness of intravenous (IV) ascorbate in treating various types of cancer. Methods: Single arm and randomized Phase I/II trials were included in this review. The PubMed, MEDLINE, and Cochrane databases were searched. Results were screened by three of the authors (GN, RP, and CJP) to determine if they met inclusion criteria, and then summarized using a narrative approach. Results: A total of 23 trials involving 385 patients met the inclusion criteria. Only one trial, in ovarian cancer, randomized patients to receive vitamin C or standard of care (chemotherapy). That trial reported an 8.75 month increase in progression-free survival (PFS) and an improved trend in overall survival (OS) in the vitamin C treated arm. Conclusion: Overall, vitamin C has been shown to be safe in nearly all patient populations, alone and in combination with chemotherapies. The promising results support the need for randomized placebo-controlled trials such as the ongoing placebo-controlled trials of vitamin C and chemotherapy in prostate cancer.

Circulating Human Papillomavirus DNA as a Biomarker of Response in Patients With Locally Advanced Cervical Cancer Treated With Definitive Chemoradiation

2018 ◽  
pp. 1-8 ◽  
Author(s):  
Kathy Han ◽  
Eric Leung ◽  
Lisa Barbera ◽  
Elizabeth Barnes ◽  
Jennifer Croke ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Fdg Pet ◽  
Residual Disease ◽  
Locally Advanced ◽  
Progression Free Survival ◽  
Advanced Cervical Cancer ◽  
Free Survival ◽  
Hpv Dna ◽  
Locally Advanced Cervical Cancer ◽  
Undetectable Plasma

Purpose To determine whether plasma human papillomavirus (HPV) DNA predates clinical recurrence and compare its accuracy with 3-month fluorodeoxyglucose positron emission tomography (FDG-PET) in locally advanced cervical cancer. Methods This prospective multicenter study accrued 23 women with stage IB to IVA cervical cancer planned for definitive chemoradiation therapy (CRT). Plasma HPV DNA was measured serially by digital polymerase chain reaction, and FDG-PET was performed at 3 months post-CRT. Results Of the 19 women with HPV+ cervical cancer included in this analysis, 32% were stage IB, 58% IIB, and 10% IIIB/IVA. Median follow-up was 24 months (range, 18 to 30 months). All patients had detectable plasma HPV DNA before treatment. Six patients had detectable plasma HPV DNA at the end of CRT, and three of them developed metastases at 3 months. Of the 13 patients with undetectable plasma HPV DNA at end of CRT, to date, only one has developed recurrence. Six of those 13 patients had a positive 3-month FDG-PET with no definite residual disease on subsequent imaging or clinical examination to date, and four of these six had undetectable plasma HPV DNA at 3 months. Patients with undetectable plasma HPV DNA at end of CRT had significantly higher 18-month progression-free survival than those with detectable plasma HPV DNA (92% v 50%; P = .02). The area under the receiver operating characteristic curve (accuracy) of 3-month plasma HPV DNA and 3-month FDG-PET imaging for predicting recurrence at 18 months were 77% and 60%, respectively ( P = .008). Conclusion Detectable plasma HPV DNA at end of CRT predates the clinical diagnosis of metastases and is associated with inferior progression-free survival. Moreover, 3-month plasma HPV DNA level is more accurate than 3-month FDG-PET imaging in detecting residual disease. The clinical utility of plasma HPV DNA detection for guiding adjuvant/salvage therapy should be evaluated in future studies.

Detection and impact of minimal residual disease on outcome of chronic lymphocytic leukemia

2012 ◽  
Vol 153 (41) ◽  
pp. 1622-1628
Author(s):  
Márk Plander ◽  
Judit Skrapits ◽  
Tünde Bozsó ◽  
Tamás Szendrei ◽  
János László Iványi
Keyword(s):  
Overall Survival ◽  
Chronic Lymphocytic Leukemia ◽  
Complete Remission ◽  
Minimal Residual Disease ◽  
Residual Disease ◽  
Single Agent ◽  
Progression Free Survival ◽  
Lymphocytic Leukemia ◽  
Free Survival ◽  
Minimal Residual

Introduction: Minimal residual disease is associated with longer overall survival in patients with chronic lymphocytic leukemia. Aim: The aim of the authors was to determine the clinical significance of remission and minimal residual disease on the survival of patients with chronic lymphocytic leukemia. Methods: Data from 42 first-line treated patients with chronic lymphocytic leukemia were analyzed. Minimal residual disease was determined by flow cytometry. Results: Overall response and complete remission was achieved in 91%, 86%, 100% and 87%, 0%, 60% of patients with fludarabine-based combinations, single-agent fludarabine and cyclophosphamide + vincristin + prednisolone regimen, respectively. Minimal residual disease eradication was feasible only with fludarabine-based combinations in 60% of these cases. The ratio of minimal residual disease was 0.5% on average. During a median follow-up period lasting 30 months, the overall survival of patients with fludarabine-resistant disease proved to be significantly shorter (p = 0.04), while complete remission without minimal residual disease was associated with significantly longer progression free survival (p = 0.02). Conclusion: Only fludarabine-based combinations were able to eradicate minimal residual disease in patients with chronic lymphocytic leukemia. Complete remission without minimal residual disease may predict longer progression free survival in these patients. Orv. Hetil., 2012, 153, 1622–1628.

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