Low-dose Oral Cyclophosphamide Research Articles

Combined oral low-dose cyclophosphamide endocrine therapy may improve clinical response among patients with metastatic breast cancer via Tregs in TLSs

Despite limited research on refractory and/or endocrine therapy failure in elderly metastatic breast cancer (MBC) patients, a prior study showed that low-dose oral cyclophosphamide (CY) can improve the overall survival rate of MBC patients, possibly through the immunoregulation of regulatory T cells (Tregs). We preliminarily investigated the combination of endocrine therapy (ET) with oral low-dose CY as salvage therapy in elderly patients via peripheral blood regulatory T-cell analyses. In addition, we evaluated the associations of tumor tertiary lymphoid structures (TLSs) with therapeutic outcomes. HR+/HER2− advanced breast cancer patients who received low-dose CY combined with ET or ET only from April 2015 to August 2021 were enrolled in this retrospective study. The primary outcome was the clinical control rate (CCR), and the secondary outcome was progression-free survival (PFS). Circulating T lymphocyte subpopulations represented by Tregs were monitored during treatment by flow cytometry methods. TLSs wereconfirmed by hematoxylin–eosin staining of pretreatment specimens, and CD3, CD4, and Foxp3 were detected using Opal multicolor immunofluorescence. A total of 85 patients who received CY + ET and 50 patients who received ET only were enrolled, the percentage of patients who received CCR was 73% (62/85) vs. 70% (45/50), and the objective response rate (ORR) was 28% (24/85) vs. 24% (12/50). No deaths occurred during the study period. The mean PFS time was 13 vs. 11 months (P = 0.03). In the CY + ET group, decreases in CD4+/CD25+/Foxp3+ T cells (P < 0.001) were favorable for both clinical control and prolonged PFS (P < 0.001). Compared with patients without TLSs, those with TLSs were more likely to have better clinical control and PFS (mean time = 6 months), and a greater number of Treg cells during TLS pretreatment correlated with longer PFS (P = 0.043). Oral low-dose CY combined with standard ET exerts immunological effects by decreasing Treg levels to achieve improved clinical responses. Moreover, patients with TLSs might benefit more from such therapy than those without TLSs, and a high Treg cell count in TLSs before treatment predicts better therapeutic efficacy.

Sustained Survival Benefit in Recurrent Medulloblastoma by a Metronomic Antiangiogenic Regimen

Medulloblastoma recurrence in patients who have previously received irradiation has a dismal prognosis and lacks a standard salvage regimen. To evaluate the response rate of pediatric patients with medulloblastoma recurrence using an antiangiogenic metronomic combinatorial approach (Medulloblastoma European Multitarget Metronomic Anti-Angiogenic Trial [MEMMAT]). This phase 2, investigator-initiated, multicenter nonrandomized controlled trial assessed 40 patients with relapsed or refractory medulloblastoma without a ventriculoperitoneal shunt who were younger than 20 years at original diagnosis. Patients were enrolled between April 1, 2014, and March 31, 2021. Treatment consisted of daily oral thalidomide, fenofibrate, celecoxib, and alternating 21-day cycles of low-dose (metronomic) oral etoposide and cyclophosphamide, supplemented by intravenous bevacizumab and intraventricular therapy consisting of alternating etoposide and cytarabine. The primary end point was response after 6 months of antiangiogenic metronomic therapy. Secondary end points included progression-free survival (PFS), overall survival (OS), and quality of life. Adverse events were monitored to assess safety. Of the 40 patients (median [range] age at treatment start, 10 [4-17] years; 25 [62.5%] male) prospectively enrolled, 23 (57.5%) achieved disease control after 6 months of treatment, with a response detected in 18 patients (45.0%). Median OS was 25.5 months (range, 10.9-40.0 months), and median PFS was 8.5 months (range, 1.7-15.4 months). Mean (SD) PFS at both 3 and 5 years was 24.6% (7.9%), while mean (SD) OS at 3 and 5 years was 43.6% (8.5%) and 22.6% (8.8%), respectively. No significant differences in PFS or OS were evident based on molecular subgroup analysis or the number of prior recurrences. In patients demonstrating a response, mean (SD) overall 5-year PFS was 49.7% (14.3%), and for patients who remained progression free for the first 12 months of treatment, mean (SD) 5-year PFS was 66.7% (16.1%). Treatment was generally well tolerated. Grade 3 to 4 treatment-related adverse events included myelosuppression, infections, seizures, and headaches. One heavily pretreated patient with a third recurrence died of secondary acute myeloid leukemia. This feasible and well-tolerated MEMMAT combination regimen demonstrated promising activity in patients with previously irradiated recurrent medulloblastoma. Given these results, this predominantly oral, well-tolerated, and outpatient treatment warrants further evaluation. ClinicalTrials.gov Identifier: NCT01356290.

Alveolar rhabdomyosarcoma has superior response rates to vinorelbine compared to embryonal rhabdomyosarcoma in patients with relapsed/refractory disease: A meta-analysis.

Patients with alveolar rhabdomyosarcoma (ARMS) have inferior outcomes compared to patients with embryonal rhabdomyosarcoma (ERMS) and more effective chemotherapy options are needed for these patients. Vinorelbine is a semisynthetic vinca alkaloid that has clinical activity in relapsed rhabdomyosarcoma (RMS) when used alone or in combination with cyclophosphamide. The goal of our study was to evaluate whether RMS histology subtype influences response rate to vinorelbine alone or in combination. Five Phase 2 trials that enrolled RMS patients were included in the meta-analysis. Two studies evaluated vinorelbine alone, two studies evaluated vinorelbine in combination with low dose oral cyclophosphamide, and one study evaluated vinorelbine and intravenous cyclophosphamide in combination with temsirolimus or bevacizumab. All RMS patients had relapsed or refractory disease and had received at least one prior therapy. Response was reported according to RECIST1.1 and was defined as a complete or partial response. Response data was obtained from published results or from trial principal investigator. RMS NOS patients were grouped with ERMS patients for this analysis. Summary estimates comparing differences between ARMS and ERMS response rates were generated using a random-effects model to account for heterogeneity among the studies. One hundred fifty-six enrolled patients evaluable for response were included in the meta-analysis, 85 ARMS, 64 ERMS and 7 RMS-NOS. The combined effect generated from the random-effects model demonstrated a 41% increase (p = 0.001, 95% CI; 0.21-0.60) in response to vinorelbine as a single agent or in combination in patients with ARMS compared to patients with ERMS. There was no significant difference in the rate of progressive disease between patients with ARMS compared to ERMS (p = 0.1, 95%CI; -0.26-0.02). Vinorelbine is an active agent for the treatment of relapsed or refractory RMS and a meta-analysis of Phase 2 studies shows that radiographic responses in patients with ARMS were significantly higher than ERMS or RMS-NOS. These data support further investigation of vinorelbine in newly diagnosed patients with RMS particularly those with alveolar histology.

Improved Long-Term Survival of Patients with Recurrent Medulloblastoma Treated with a "MEMMAT-like" Metronomic Antiangiogenic Approach.

Simple SummaryAbout 30% of patients with medulloblastoma experience recurrence, which is usually incurable despite intensive chemotherapy. The aim of our retrospective study was to evaluate a novel combinatorial metronomic antiangiogenic approach (“MEMMAT-like”) for recurrent medulloblastoma consisting of five oral drugs, an intravenous antibody against vascular endothelial growth factor, and intrathecal therapy. The study, conducted between 2006 and 2016, included 29 consecutive patients with first or multiple recurrences treated according to this “MEMMAT-like” strategy and confirmed a significantly longer median overall survival than in previously reported studies. As of 07/2022, 9/29 patients are alive 86 to 164 months after recurrence. Treatment was primarily out-patient and well-tolerated. Toxicities did occur but were manageable. The novel combination significantly improved overall and progression-free survival for patients with recurrent medulloblastoma. A formal study (MEMMAT; ClinicalTrials.gov Identifier: NCT01356290) has been completed and is currently being evaluated.Medulloblastoma (MB) recurrence is usually incurable despite intensive therapy including high-dose chemotherapy. An evolving alternative approach to conventional chemotherapy aims at interfering with tumor angiogenesis at different levels. We report on a novel combinatorial metronomic antiangiogenic approach. The study is a retrospective observational study of 29 consecutive patients with first or multiple recurrences prospectively treated according to the MEMMAT strategy (“MEMMAT-like”) before the formal protocol (MEMMAT; ClinicalTrials.gov Identifier: NCT01356290) started. The study period was 11/2006 to 06/2016. Treatment consisted of daily oral thalidomide, fenofibrate, celecoxib, and alternating 21-day cycles of low-dose oral etoposide and cyclophosphamide supplemented by IV bevacizumab and intraventricular therapy consisting of alternating etoposide and liposomal cytarabine. Median overall survival (OS) after recurrence for the whole group was 29.5 months, OS was 48.3 ± 9.3% at three years and 34.5 ± 8.8% at five years, and progression-free survival was 42.0 ± 9.5% at three years and 29.4 ± 9% at five years. As of 07/2022, 9/29 patients are alive 86 to 164 months after the recurrence that prompted the “MEMMAT-like” therapy. Treatment was primarily out-patient and generally well-tolerated. Toxicities did occur but were manageable. In conclusion, antiangiogenic therapy according to the MEMMAT strategy increased median OS of patients with recurrent MB and may lead to long-term survival. Adherence to the protocol, including intraventricular therapy, appears important.

Combination of Rituximab, Low-Dose Cyclophosphamide, and Prednisone for Primary Membranous Nephropathy: A Case Series With Extended Follow Up

B-cell depletion with rituximab has emerged as a first-line therapy for primary membranous nephropathy (MN). However, most patients do not achieve complete remission with rituximab monotherapy. In this case series, we report longer-term remission and relapse rates, anti-phospholipase A2 receptor (PLA2R) antibody levels, B-cell levels, and serious adverse events in patients with primary MN who received rituximab combined with an initial short course of low-dose oral cyclophosphamide and a course of rapidly tapered prednisone. Single-center retrospective case series. 60 consecutive patients with primary MN treated with the combination of rituximab, low-dose cyclophosphamide, and prednisone at the Vasculitis and Glomerulonephritis Center at the Massachusetts General Hospital. After treatment initiation, median follow-up was 38 (interquartile range [IQR], 25-62) months; 100% of patients achieved partial remission, defined as a urinary protein-creatinine ratio (UPCR)< 3 g/g and a 50% reduction from baseline, at a median of 3.4 months. By 2 years after treatment initiation, 83% achieved complete remission, defined as a UPCR< 0.3 g/g. The median time to complete remission was 12.4 months. Immunologic remission (defined by an anti-PLA2R titer < 14 RU/mL) was achieved by 86% and 100% of anti-PLA2R seropositive patients (n = 29) at 3 and 6 months, respectively, after treatment initiation. After 1 year, the median UPCR fell from 8.4 (IQR, 5.0-10.7) to 0.3 (IQR, 0.2-0.8) g/g (P< 0.001). No patient relapsed throughout the duration of B-cell depletion. Relapse occurred in 10% of patients at 2 years after the onset of B-cell reconstitution following the last rituximab dose. Over a combined follow-up time of 228 patient-years, 18 serious adverse events occurred. One death occurred unrelated to treatment or primary MN, and 1 patient progressed to kidney failure requiring kidney replacement therapy. Absence of a comparison group. All patients with primary MN treated with combination therapy achieved partial remission and most achieved a durable complete remission with an acceptable safety profile.

Vaccine-Induced Intratumoral Lymphoid Aggregates Correlate with Survival Following Treatment with a Neoadjuvant and Adjuvant Vaccine in Patients with Resectable Pancreatic Adenocarcinoma.

Immunotherapy is currently ineffective for nearly all pancreatic ductal adenocarcinomas (PDAC), largely due to its tumor microenvironment (TME) that lacks antigen-experienced T effector cells (Teff). Vaccine-based immunotherapies are known to activate antigen-specific Teffs in the peripheral blood. To evaluate the effect of vaccine therapy on the PDAC TME, we designed a neoadjuvant and adjuvant clinical trial of an irradiated, GM-CSF-secreting, allogeneic PDAC vaccine (GVAX). Eighty-seven eligible patients with resectable PDAC were randomly assigned (1:1:1) to receive GVAX alone or in combination with two forms of low-dose cyclophosphamide. Resected tumors following neoadjuvant immunotherapy were assessed for the formation of tertiary lymphoid aggregates (TLA) in response to treatment. The clinical endpoints are disease-free survival (DFS) and overall survival (OS). The neoadjuvant treatment with GVAX either alone or with two forms of low-dose cyclophosphamide is safe and feasible without adversely increasing the surgical complication rate. Patients in Arm A who received neoadjuvant and adjuvant GVAX alone had a trend toward longer median OS (35.0 months) than that (24.8 months) in the historical controls who received adjuvant GVAX alone. However, Arm C, who received low-dose oral cyclophosphamide in addition to GVAX, had a significantly shorter DFS than Arm A. When comparing patients with OS > 24 months to those with OS < 15 months, longer OS was found to be associated with higher density of intratumoral TLA. It is safe and feasible to use a neoadjuvant immunotherapy approach for PDACs to evaluate early biologic responses. In-depth analysis of TLAs is warranted in future neoadjuvant immunotherapy clinical trials.

Multiagent chemotherapy including IrIVA regimen and maintenance therapy in the treatment of desmoplastic small round cell tumor.

This study reports the treatment feasibility and efficacy of a novel multiagent intensive treatment program for young patients with desmoplastic small round cell tumor. This small series includes three patients and should be seen as a first suggestion of integration of the dose density and the maintenance chemotherapy concept. The IrIVA regimen (irinotecan, ifosfamide, vincristine, and actinomycin-D) is added-used at a short interval between chemotherapy administrations-at more classic intensive ifosfamide-based regimens. The vinorelbine and low-dose oral cyclophosphamide maintenance therapy is added at the end of conventional chemotherapy to achieve an antiangiogenic effect.

Unusual Case of Hepatic Sinusoidal Obstruction Syndrome Induced By Low Dose Oral Cyclophosphamide

Hepatic sinusoidal obstruction syndrome (SOS) has been reported in patients receiving high dose intravenous (IV) cyclophosphamide especially as a part of preparative regimen for hematopoietic stem cell transplantation. Hepatic SOS from low dose oral cyclophosphamide has not been reported. Here we present a rare case of hepatic SOS induced by low dose oral cyclophosphamide. A 78-year-old male with history of coronary artery disease status post coronary artery bypass graft (CABG) was initially seen in hematology clinic for evaluation of normocytic anemia. During workup, bone marrow biopsy revealed NK cell large granular lymphocytic leukemia (LGL). He was then started on low dose oral cyclophosphamide 50 mg daily. After 2 months, his dose was reduced to 25 mg daily due to severe neutropenia. He then tolerated cyclophosphamide well and his hemoglobin (Hb) improved from his baseline 8 gm/dl to 12 gm/dl in 4 months. After 6 months of treatment, he was admitted to the hospital for abdominal distension, ascites and 15 pounds weight gain over 3 weeks. Labs most prominent on admission were Hb of 12.5 gm/dL , WBC 5.3 x 103/µL, Platelets 197 x 103/µL, total bilirubin 1.6 mg/dL, aspartate aminotransferase (AST) 89 U/L , alanine aminotransferase (ALT) 35 U/L and alkaline phosphatase (ALP) 283 U/L. Workup of ascites included abdominal paracentesis which revealed serum ascites albumin gradient(SAAG) &amp;lt;1.1 and fluid cytology was negative for carcinoma. Ultrasound of abdomen showed diffuse parenchymal heterogeneity and increased echogenicity of liver with patent hepatic vessels with normal direction of blood flow. Echocardiogram revealed preserved left ventricular systolic function with estimated left ventricular ejection fraction of 60%. He then underwent transjugular liver biopsy which revealed chronic lymphoproliferative disorder of NK cells, prominent centrilobular sinusoidal dilatation and congestion, lobular disarray, cholestasis and sinusoidal fibrosis suggestive of veno-occlusive disease secondary to drug/toxin induced liver injury. The Naranjo adverse drug reaction probability scale indicated a probable relationship between hepatic SOS and cyclophosphamide. Cyclophosphamide was held. Bone marrow biopsy showed the patient was in remission. His liver enzymes are improving and hematologic counts continue to be stable while on observation. High dose of IV cyclophosphamide given as myeloablative therapy in combination of total body irradiation or busulfan (or other agents) in preparation for hematopoietic stem cell transplantation can induce hepatic SOS, which can be severe leading to acute liver failure and death. The diagnosis is usually based on clinical features of tender hepatomegaly, weight gain, ascites and jaundice. Liver biopsy is usually diagnostic. Mechanism of injury is related to direct toxic effects of cyclophosphamide on sinusoidal cells in the liver, causing their necrosis and release into the sinusoids, obstruction and obliteration of hepatic veins. This case demonstrates that hepatic SOS can also be caused by low dose oral cyclophosphamide. Given this rare occurrence, it is prudent for the clinicians to keep an open mind and consider hepatic SOS as a potential side effect even with oral cyclophosphamide. Disclosures Yacoub: Novartis: Speakers Bureau; Agios: Honoraria, Speakers Bureau; Incyte: Speakers Bureau; Hylapharm: Current equity holder in private company; Cara Therapeutics: Current equity holder in publicly-traded company; Ardelyx: Current equity holder in publicly-traded company; Dynavax: Current equity holder in publicly-traded company; Roche: Other: Support of parent study and funding of editorial support.

A Randomized Phase II, Open Label, Study of Daratumumab, Weekly Low-Dose Oral Dexamethasone and Cyclophosphamide with or without Pomalidomide in Patients with Relapsed and Refractory Multiple Myeloma

A Randomized Phase II, Open Label, Study of Daratumumab, Weekly Low-Dose Oral Dexamethasone and Cyclophosphamide with or without Pomalidomide in Patients with Relapsed and Refractory Multiple Myeloma

Low-dose oral cyclophosphamide therapy reduces atherosclerosis progression by decreasing inflammatory cells in a murine model of atherosclerosis

BackgroundAtherosclerosis is a chronic inflammatory disease responsible for most cases of heart disease and stroke in Western countries. The cytotoxic drug cyclophosphamide (CPA) can modulate immune functions, and it has therefore been used to treat patients with autoimmune diseases. Extension of survival of patients with severe atherosclerosis has been reported after CPA treatment, but the underlying mechanism is still poorly understood. Methods and resultsWe have investigated the effects of CPA in a murine model of atherosclerosis. Continuous oral administration of low-dose CPA (20 mg/kg/day) prevented atherosclerosis in apolipoprotein E-deficient (apoE-/-) mice fed with a high fat diet. After 12 weeks, CPA treatment delayed progression of atherosclerosis in the mice (9.92% vs 3.32%, P < 0.05, n = 7) and reduced the macrophage content of plaques (1.228 vs 0.2975 mm2, P < 0.001). Flow cytometry (FACS) showed that, in peripheral blood and spleen cells, the numbers of B cells and inflammatory T cells (Th1 cells) decreased, and inflammatory monocytes also decreased. However, there were no differences in the bone marrow cells between the two groups. The mRNA levels in the aorta showed significantly decreased inflammatory cytokine (interleukin-6) (P < 0.05), and tended to increase anti-inflammatory cytokine (argininase-1), but no significant differences between the two groups. High dose CPA has cardiotoxicity, but the dose used in this study did not show significant cardiotoxicity. ConclusionsThe results demonstrate that oral treatment with CPA inhibits initiation and progression of atherosclerosis in the apoE-/- mouse model through immunomodulatory effects on lymphoid and inflammatory cells.

Efficacy and Safety of Nivolumab Combined with Daratumumab with or without Low-Dose Cyclophosphamide in Relapsed/Refractory Multiple Myeloma; Interim Analysis of the Phase 2 Nivo-Dara Study

Efficacy and Safety of Nivolumab Combined with Daratumumab with or without Low-Dose Cyclophosphamide in Relapsed/Refractory Multiple Myeloma; Interim Analysis of the Phase 2 Nivo-Dara Study

Prospective, Multicentric Phase II Randomized Trial Comparing the Efficacy of Methotrexate or Cyclophosphamide in Large Granular Lymphocytic Leukemia: A French National Study. Report on the Interim Analysis

Introduction Large granular lymphocyte (LGL) leukemia is characterized by a clonal expansion of CD3+ cytotoxic T or CD3- NK cells. Prominent clinical features include neutropenia, anemia and autoimmune-associated diseases such as rheumatoid arthritis (RA). Although the disease is usually chronic and indolent, some patients may be symptomatic and require treatment. No standard therapy has been established due to the absence of prospective clinical trials. So far, low dose methotrexate, oral cyclophosphamide, and cyclosporine represent the 3 main options for initial therapy. In 2014, we launched a prospective clinical trial comparing methotrexate to cyclophosphamide in previously-untreated patients with LGL leukemia in need of treatment. Patients and methods The study was designed as a multicentric, national, open label, randomized, controlled trial on two parallel groups, comparing methotrexate and cyclophosphamide. Patients were included if they had at least one of the following indications of treatment: isolated severe neutropenia (ANC &amp;lt;0.5x109/L) or neutropenia (ANC &amp;lt;1.5x109/L) with infections, anemia requiring transfusions or symptomatic anemia, associated complications such as systemic diseases or auto-immune diseases resistant to steroids and/or immunomodulating agents (colchicin, disulone, hydrochloroquine). They were randomly assigned to receive either methotrexate (10 mg/m²/w) or cyclophosphamide (100 mg/d) for 4 months. Responders at M4 continued with the same treatment until M12 (cyclophosphamide was then delivered at 50 mg/d). Non-responders at M4 were randomly assigned to receive either cyclosporine (3 mg/kg/d) or the drug which had not been administered at the first randomization (methotrexate or cyclophosphamide). Response was assessed using previously published criteria (Lamy T, Blood 123:1182, 2014). Complete response (CR) was defined as a normalization of clinical exam (disappearance of splenomegaly or associated autoimmune symptoms) and a complete normalization of blood counts. Partial response (PR) was defined as an improvement in blood counts which did not meet criteria for complete remission (e.g., ANC &amp;gt;0.5x109/L or decrease of transfusion requirements). Treatment failure was defined as no response or any response which did not meet the above-mentioned criteria within four months after the beginning of treatment. To stop the trial as soon as sufficient information was collected, a sequential analysis was planned each time 20 patients were included and evaluated using the triangular test (Sébille V, Bellissant E. Fundam Clin Pharmacol. 2003;17(5):505-16). The primary endpoint was the hematological CR rate evaluated at M4 (binary endpoint). Secondary endpoints were overall response rate (ORR) at M4, M8 and M12, time to relapse. For non-responders at M4, cyclosporine was compared to the treatment which had not been administered during the first phase. Results From Nov 2013 to July 2019, 99 patients met inclusion criteria among which 96 were randomized. The baseline characteristics of these patients are shown in Table1. STAT3 mutation was observed 52% of cases. After the 4th sequential analysis performed on the first 80 patients evaluable for response at M4, the sample path remained in the continuation region of the triangular test. Thus, the trial has to be continued. At M4, 13 patients were in CR (16.3%) and 29 patients were in PR (36.3%), ORR was 52.6%, 36 patients were considered as refractory and underwent a second randomization: 18 patients received cyclosporine and 17 received methotrexate or cyclophosphamide. Conclusions This first prospective randomized clinical trial in LGL leukemia shows that the CR after first line therapy using either methotrexate or cyclophosphamide is relatively low (&amp;lt; 20%). Recruitment is still ongoing to assess if there is a difference in terms of response between the two drugs. Predictive biomarkers of response will be presented at the meeting. Regarding a 52% of incidence of Stat3 mutation (higher than that previously published), Jak/Stat targeted therapy should be prospectively evaluated in this disease. Disclosures Houot: Bristol Myers Squibb: Honoraria; Merck Sharp Dohme: Honoraria. Gyan:Pfizer: Honoraria. Feugier:janssen: Honoraria, Research Funding, Speakers Bureau; abbvie: Honoraria, Research Funding, Speakers Bureau; gilead: Honoraria, Research Funding, Speakers Bureau; roche: Honoraria, Research Funding, Speakers Bureau.

A Randomized Phase II, Open Label, Study of Daratumumab, Weekly Low-Dose Oral Dexamethasone and Cyclophosphamide with or without Pomalidomide in Patients with Relapsed and Refractory Multiple Myeloma

A Randomized Phase II, Open Label, Study of Daratumumab, Weekly Low-Dose Oral Dexamethasone and Cyclophosphamide with or without Pomalidomide in Patients with Relapsed and Refractory Multiple Myeloma

Phase 1 study of everolimus and low-dose oral cyclophosphamide in patients with metastatic renal cell carcinoma

mTOR inhibitors are frequently used in the treatment of metastatic renal cell cancer (mRCC). mTOR regulates cell growth, proliferation, angiogenesis, and survival, and additionally plays an important role in immune regulation. Since mTOR inhibitors were shown to benefit immunosuppressive regulatory T-cell (Treg) expansion, this might suppress antitumor immune responses. Metronomic cyclophosphamide (CTX) was shown to selectively deplete Tregs. This study was, therefore, designed to determine the optimal dosage and schedule of CTX when combined with everolimus to prevent this potentially detrimental Treg expansion. In this national multi-center phase I study, patients with mRCC progressive on first line anti-angiogenic therapy received 10 mg everolimus once daily and were enrolled into cohorts with different CTX dosages and schedules. Besides immune monitoring, adverse events and survival data were monitored. 40 patients, 39 evaluable, were treated with different doses and schedules of CTX. Combined with 10 mg everolimus once daily, the optimal Treg depleting dose and schedule of CTX was 50 mg CTX once daily. 23 (59%) patients experienced one or more treatment-related ≥ grade 3 toxicity, mostly fatigue, laboratory abnormalities and pneumonitis. The majority of the patients achieved stable disease, two patients a partial response. Median PFS of all cohorts was 3.5 months. In conclusion, the optimal Treg depleting dose and schedule of CTX, when combined with everolimus, is 50 mg once daily. This combination leads to acceptable adverse events in comparison with everolimus alone. Currently, the here selected combination is being evaluated in a phase II clinical trial.Trial registrationNCT01462214.

Use of Oral Low-dose Cyclophosphamide Therapy in Patients With Refractory Extensive Crohnʼs Disease

Introduction Cyclophosphamide (CPM) is one of the oldest chemotherapeutic agents available, which also has immunosuppressive properties. It was first used for inflammatory bowel disease (IBD) in 1985, when given to 4 patients who developed pancreatitis on azathioprine. The first case series using pulse IV CPM for steroid-refractory IBD was described in 2003. Case presentation We describe a case of a 23-year-old Caucasian male diagnosed with Crohn's disease (CD) at 14 years of age (Montreal Classification A1L1L4B1p). He was initially treated with infliximab but developed an anaphylactic reaction prompting a transition to adalimumab combined with methotrexate. His disease, however, remained active involving the entire small bowel. He was started on vedolizumab with methotrexate but did not achieve remission. A subsequent transition to ustekinumab allowed tapering off prednisone, but 1 month later, he developed symptoms, which persisted despite dose escalation. A short course of mycophenolate mofetil was attempted but it was unsuccessful.By the end of 2016, he developed arthralgias and osteoporosis, both attributed to steroid use. Given the persistence of inflammation despite conventional medical therapy, he was started on oral CPM (1.5 mg/kg/day), alongside prednisone. At 10 days follow-up, the patient reported significant improvement in his energy levels and abdominal pain. His symptoms continued improving, and he was able to taper prednisone to 15 mg daily at 5 weeks from starting CMP, and achieve clinical remission. Two months into starting therapy, he noted worsening of his symptoms with loose stools, nausea and weight loss. However, CRP (C reactive protein) was trending down. Discontinuation of abaloparatide, which was taken concomitantly, lead to symptom resolution. At his most recent follow-up visit, at 24 weeks from starting CPM, the patient was in clinical remission, on CMP and prednisone 7.5 mg/day. Discussion: The use of oral low-dose CPM offers an improvement in efficacy but also a mild increase in the rate of leukopenia. We chose the oral regimen for its rapid onset, efficacy and steroid-sparing properties, with the convenience of avoiding IV administration. A lower dose was selected to reduce the risk of leukopenia. Besides the 4 cases described in 1985, this is the first description of oral CPM use for induction of remission in a patient with CD. This case highlights another treatment option for highly refractory IBD patients.

Whether low-dose metronomic oral cyclophosphamide improves the response to docetaxel in first-line treatment of non-triple-negative metastatic breast cancer

Oral metronomic chemotherapy may target tumor cells indirectly via antiangiogenic activity, restoration of anticancer immune response, or induction of tumor dormancy. We initiated the single-center, randomized, open-label, phase II study to determine whether the addition of metronomic cyclophosphamide to docetaxel (T) (w/o trastuzumab) improves overall response rate (ORR) as first-line treatment among patients with non-triple-negative metastatic breast cancer (MBC). Eligible patients with previously untreated non-triple-negative MBC were randomly assigned (1:1) to receive 3-weekly cycles of Metro-TC (T 75mg/m2, d1 plus oral cyclophosphamide 50 mg daily) or T alone. All patients received treatment until disease progression, unacceptable toxicity, or withdrawal of consent. The primary endpoint was ORR. Finally, 35 patients were randomized to Metro-TC group while 31 to T group. Median treatment cycles of T for both groups were 8. ORR was not improved by addition of metronomic cyclophosphamide to T (71.4% vs. 51.6%; P = 0.09). There was no statistically significant difference with regard to progression free survival (median 18.5 vs. 11.7 months; P = 0.07) or overall survival (median 33.7 vs. 33.6 months; P = 0.84) between the two group. Grade 3/4 adverse events (eg. neutropenia [100% vs. 100%], febrile neutropenia [29% vs. 29%], and neurotoxicity [6% vs. 3%]) were also comparable. There were no treatment-related deaths. We conclude that concomitant administration of metronomic cyclophosphamide and T does not appear to be a significantly active schedule for first-line treatment of non-triple-negative MBC.

Abstract P6-12-08: Phase I study of low dose oral cyclophosphamide (C) plus the poly-ADP-ribose- polymerase (PARP) inhibitor veliparib (V) in women with HER2/neu-negative inoperable locally advanced/metastatic breast cancer (MBC): NCI P8853

Abstract BACKGROUND: PARP, an essential nuclear enzyme, is involved in the recognition of DNA damage and facilitation of DNA base-excision repair (BER). PARP inhibition sensitizes tumor cells to cytotoxic agents which induce DNA damage, including C. Metronomic dosing of C may optimize potential for synergy with PARP inhibitors, and also inhibits angiogenesis (Kerbel et al, Nat Rev Cancer, 4:423-36, 2004) and may enhance anti-tumor immunity (Ghiringhelli et al. Cancer Immunol Immunother 56:641–648, 2007) V is an oral small molecule inhibitor of PARP which potentiates the antineoplastic activity of DNA damaging agents such as C in MX-1 breast xenograft model (Donawho et al Clin Cancer Res 13:2728-37, 2007). We performed a phase I trial of metronomic dose oral C plus V in patients with MBC. METHODS: The primary objective was to determine the safety and identify the recommended phase II dose (RPTD) of the combination of low-dose oral C once daily in combination with V (100, 200, 300 mg) administered BID for 21 days using a standard 3+3 design. Eligibility included HER2/neu negative MBC, ECOG PS 0-1, and at least 1 prior chemotherapy regimen for MBC. Dose limiting toxicity (DLT) was defined as any Grade 3 non-hematological toxicity or Grade 4 thrombocytopenia/neutropenia occurring during cycle 1. After the RPTD of V was shown to be 200 mg BID with C 50 mg daily, the trial was amended to increase the C dose to 75, 100 and then 125 mg daily until hematologic toxicity was dose-limiting. RESULTS: 31 patients were enrolled, 19 treated with 50 mg of C and 12 treated at higher doses (75-125 mg), with V doses ranging from 50 mg-300 mg BID (see table);5 patients with not evaluable due to rapid disease progression (N=2), non-compliance (N=2), or tumor pain that was not a DLT (N=1). Median age was 52 years (28-72 years), 14 (45 %) had triple negative disease, all had at least 1 prior chemotherapy regimen for metastasis (median 2, range 1-8), and, 7 had germline BRCA mutations, (3 BRCA1 and 4 BRCA2). When combined with 50 mg C daily, RPTD of V was 200 mg PO BID, with nausea being DLT at 300 mg BID. DLT was not observed in any of the 9 additional patients. The median number of cycles given was 3 (range 1-14). Clinical benefit (response or stable disease for at least 24 weeks) occurred in 3/7 (43%), 1/3 (33%) and 1/16(6%) for BRCA mutated, BRCA negative and BRCA unknown, respectively. Median progression-free survival was 4.3 months (1.2-10.9 months) for BRCA mutated patients and 2 months (0.7-10 months) for non-mutated. CONCLUSIONS: The combination of oral continuous dosing of V (200 mg PO BID) with metronomic C (50, 75, 100 and 125 mg daily) is well tolerated and shows antitumor activity in patients with BRCA mutation associated MBC. The RPTD is C 125 mg daily plus V 200 mg BID, although further escalation of the C dose may be feasible since DLT was not seen at this dose level. Dose LevelsDose Level# Patients/Evaluable# DLTType of DLTDL 1 :V 50mg , C 50mg3/30 DL 2 :V 100 mg, C 50mg4/30 DL 3 :V 200 mg, C 50mg6/61HeadacheDL 4 :V 300 mg, C 50mg6/52Nausea (N=2)DL 3A :V 200 mg; C 75mg3/30 DL 3B :V 200 mg, C 100mg6/30 DL 3C :V 200 mg, C 125mg3/30 Citation Format: Anampa JD, Patel M, Pellegrino C, Fehn K, Makower D, Oh S-y, Noah K, Chen A, Sparano JA, Andreopoulou E. Phase I study of low dose oral cyclophosphamide (C) plus the poly-ADP-ribose- polymerase (PARP) inhibitor veliparib (V) in women with HER2/neu-negative inoperable locally advanced/metastatic breast cancer (MBC): NCI P8853 [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P6-12-08.

Once-weekly Bortezomib in Combination with Reduced-dose Dexamethasone and Continuous Low-dose Oral Cyclophosphamide for Elderly Patients with Multiple Myeloma

CyBorD is one of the most effective triplet regimens for both transplant-eligible and ineligible patients with multiple myeloma. In comparison, once-weekly bortezomib induction therapy with a reduced dosage of dexamethasone (modified-CyBorD) showed less toxicity but an equally high response rate. However, this modification still resulted in bortezomib-induced PN in more than half of patients. We therefore introduced a once-weekly schedule of bortezomib combined with continuous low-dose oral cyclophosphamide and reduced dosage of dexamethasone (reduced-CyBorD) in transplantineligible patients with multiple myeloma in our hospital. A total of 32 patients, including 20 who were newly diagnosed and 12 who were refractory/resistant, were treated with reduced-CyBorD, and the regimen’s efficacy and safety were evaluated. The median age was 72 years; 17 patients were male and 15 were female. The overall response rate was 90.6% with 43.8% complete response/near complete response. The median progression-free and overall survival was 14.9 months and 43 months, respectively. Three patients (9.4%) developed grade 1 peripheral neuropathy, and no patients had to reduce or discontinue bortezomib. In conclusion, our results suggested that this reduced combination therapy might be a safe and effective approach in transplant-ineligible patients with multiple myeloma.

A Phase II Study of Pomalidomide, Daily Low Dose Oral Cyclophosphamide, and Dexamethasone in Relapsed/Refractory Multiple Myeloma

Relapsed/refractory multiple myeloma patients treated with pomalidomide and dexamethasone have an overall response rate (ORR) of ∼30% and median progression-free survival (PFS) of 4–5 months. Previ...

Phase 1/2 study of lenalidomide combined with low-dose cyclophosphamide and prednisone in lenalidomide-refractory multiple myeloma

AbstractThe prognosis of multiple myeloma (MM) patients who become refractory to lenalidomide and bortezomib is very poor, indicating the need for new therapeutic strategies for these patients. Next to the development of new drugs, the strategy of combining agents with synergistic activity may also result in clinical benefit for patients with advanced myeloma. We have previously shown in a retrospective analysis that lenalidomide combined with continuous low-dose cyclophosphamide and prednisone (REP) had remarkable activity in heavily pretreated, lenalidomide-refractory MM patients. To evaluate this combination prospectively, we initiated a phase 1/2 study to determine the optimal dose and to assess its efficacy and safety in lenalidomide-refractory MM patients. The maximum tolerated dose (MTD) was defined as 25 mg lenalidomide (days 1-21/28 days), combined with continuous cyclophosphamide (50 mg/d) and prednisone (20 mg/d). At the MTD (n = 67 patients), the overall response rate was 67%, and at least minimal response was achieved in 83% of the patients. Median progression-free survival and overall survival were 12.1 and 29.0 months, respectively. Similar results were achieved in the subset of patients with lenalidomide- and bortezomib-refractory disease as well as in patients with high-risk cytogenetic abnormalities, defined as t(4;14), t(14;16), del(17p), and/or ampl(1q) as assessed by fluorescence in situ hybridization. Neutropenia (22%) and thrombocytopenia (22%) were the most common grade 3-4 hematologic adverse events. Infections (21%) were the most common grade 3-5 nonhematologic adverse events. In conclusion, the addition of continuous low-dose oral cyclophosphamide to lenalidomide and prednisone offers a new therapeutic perspective for multidrug refractory MM patients. This trial was registered at www.clinicaltrials.gov as #NCT01352338.