scholarly journals Phase I study of the 177Lu-DOTA0-Tyr3-Octreotate (lutathera) in combination with nivolumab in patients with neuroendocrine tumors of the lung

2020 ◽  
Vol 8 (2) ◽  
pp. e000980
Author(s):  
Chul Kim ◽  
Stephen V Liu ◽  
Deepa S Subramaniam ◽  
Tisdrey Torres ◽  
Massimo Loda ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Level ◽  
Neuroendocrine Tumors ◽  
Phase I Study ◽  
Somatostatin Receptors ◽  
Atypical Carcinoid ◽  
Platinum Based Chemotherapy ◽  
Level 1 ◽  
Grade 3 ◽  
Level 2

BackgroundLutathera is a 177Lutetium-labeled somatostatin analog approved for the treatment of gastroenteropancreatic neuroendocrine tumors (NETs). Somatostatin receptors are expressed in small cell lung cancer (SCLC). Nivolumab, an anti-PD-1 antibody, may act synergistically with lutathera to generate antitumor immunity. We conducted a phase I study of lutathera plus nivolumab in patients with advanced NETs of the lung.MethodsPatients with relapsed/refractory extensive-stage SCLC (ES-SCLC), non-progressing ES-SCLC after first-line platinum-based chemotherapy, or advanced grade I-II pulmonary NETs were eligible. The primary objective was to determine the recommended phase 2 dose (RP2D). The phase I portion followed a standard 3+3 design, assessing two dose levels (dose level 1: lutathera 3.7 GBq every 8 weeks for four doses with nivolumab 240 mg every 2 weeks; dose level 2: lutathera 7.4 GBq every 8 weeks for four doses with nivolumab 240 mg every 2 weeks).ResultsNine patients were enrolled (six ES-SCLC, two pulmonary atypical carcinoid, one high-grade pulmonary neuroendocrine carcinoma). No dose-limiting toxicities (DLTs) were observed at dose level 1. At dose level 2, one patient with refractory ES-SCLC developed a DLT (grade 3 rash). The most common treatment-related adverse events (TRAEs) were lymphopenia (n=7), thrombocytopenia (n=4), anemia (n=3), and nausea (n=3). The most common grade 3 TRAE was lymphopenia (n=4). Among the seven patients with measurable disease, one patient with ES-SCLC had a partial response. Two patients with pulmonary atypical carcinoid had stable disease lasting 6 months. The RP2D was dose level 2.ConclusionsLutathera plus nivolumab was well tolerated and showed signs of antitumor activity. This combination warrants further exploration.Trial registration numberNCT03325816

A phase I trial of plinabulin in combination with nivolumab and ipilimumab in patients with relapsed small cell lung cancer (SCLC): Big Ten Cancer Research Consortium (BTCRC-LUN17-127) study.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 8570-8570
Author(s):  
Jyoti Malhotra ◽  
Nasser H. Hanna ◽  
Alberto Chiappori ◽  
Lawrence Eric Feldman ◽  
Naomi Fujioka ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Level ◽  
Dose Escalation ◽  
Phase I Study ◽  
Infusion Reaction ◽  
Phase 2 ◽  
Vascular Disrupting Agent ◽  
Level 1 ◽  
Grade 3 ◽  
Level 2

8570 Background: Plinabulin (BPI-2358) is a vascular disrupting agent with immune-enhancing function by inducing dendritic cell maturation and decreasing regulatory T cells. Preclinical studies report that plinabulin potentiates the cytotoxicity of dual checkpoint inhibition (CPI) with nivolumab and ipilimumab. Plinabulin may also reduce immune-related AEs from CPI through its phosphodiesterase-4 (PDE4) inhibitory activity which is associated with anti-inflammatory effects. We report initial results from a Phase I study assessing plinabulin in combination with nivolumab and ipilimumab. Methods: In this dose-escalation phase I study, patients with extensive-stage SCLC who had progressed on or after prior platinum-based chemotherapy (±CPI) were enrolled using a 3+3 design. The primary objective was to determine dose-limiting toxicities (DLT’s) and recommended Phase 2 dose (RP2D). Patients received nivolumab (1 mg/kg), ipilimumab (3 mg/kg) and plinabulin (as per dose escalation schema) IV on day 1 of each 21 day cycles. After completion of 4 cycles, patients continued therapy with nivolumab (240 mg) and plinabulin every 2 weeks till progression or intolerable toxicity. Patients were evaluable for DLT if they received at least 2 cycles of therapy; DLT period was defined as the first 6 weeks from C1D1. Secondary endpoints were ORR, PFS and frequency of irAEs. Correlative analysis included inflammatory biomarkers: hsCRP, ESR, SAA and haptoglobin. Results: Between 9/2018 and 11/2020, 17 patients were enrolled (1 patient withdrew consent before treatment, 16 were evaluable for safety). Median age was 59 years (range 43 to 78); 9 patients were male and 10 had received prior CPI. Eight patients were treated at dose-level 1 of plinabulin (20 mg/m2) and 8 patients at 30 mg/m2 of plinabulin (level 2); dose-level 2 was determined to be RP2D. There were 2 DLTs; 1 at dose-level 1 (grade 3 altered mental status lasting < 24 hours) and 1 at dose-level 2 (grade 3 infusion reaction). The most common treatment-related AEs (all grades) were nausea (10; 63%), infusion reaction (8; 50%), vomiting (7; 44%), diarrhea (7; 44%) and fatigue (6, 32%). Seven patients (44%) had at least one grade 3 or higher treatment-related AE; there were no treatment-related deaths. Two patients (13%) had grade 3 or higher irAE requiring steroids (1 colitis, 1 transaminitis); both at dose-level 1. At data cutoff (12/30/20), there were 3 PRs in CPI naïve patients (3/6; 50%) and 2 PRs in evaluable CPI-resistant patients (2/7; 29%). In the two CPI-resistant patients with confirmed response, the tumor reduction was 68% and 52%. Conclusions: Plinabulin in combination with nivolumab and ipilimumab was safe and well tolerated. A phase 2 study in CPI-experienced patients with relapsed SCLC is planned to confirm the preliminary signals of clinical activity and reduced immune toxicity. Clinical trial information: NCT03575793.

Phase I study of panobinostat (LBH589) and letrozole in post-menopausal women with metastatic breast cancer.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e13501-e13501 ◽  
Author(s):  
Winston Tan ◽  
Jacob B Allred ◽  
Alvaro Moreno-Aspitia ◽  
Donald W. Northfelt ◽  
James N. Ingle ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Metastatic Breast Cancer ◽  
Phase I ◽  
Dose Level ◽  
Phase I Study ◽  
Metastatic Breast ◽  
Level 1 ◽  
Grade 3 ◽  
Level 2

e13501 Background: Loss of estrogen receptor alpha gene expression has been associated with insensitivity to endocrine therapy in human breast cancer patients. Histone deacetylase (HDAC) inhibitors have recently been found to restore sensitivity to the estrogen receptor by modulation of the estrogen and progesterone receptors. This had been shown with both aromatase and tamoxifen refractory and in triple negative cell lines . We performed a Phase I study of the combination of LBH589 (panobinostat) and letrozole to evaluate safety and tolerability in patients with metastatic breast cancer prior to the performance of a phase II trial. Methods: We enrolled postmenopausal women with metastatic breast cancer, ECOG PS 0 or 1, ANC>1500/mm3, platelets>100,000/mm3, normal total bilirubin, and ALT/AST adequate laboratory tests were eligible. Letrozole dose was 2.5 mg/day orally. Dose of LBH589: Level 1, 20 mg orally three times weekly; Level 2, 30 mg orally three times a week. Results: 12 patients (dose level 1:6 patients, dose level 2: 6 patients) have been enrolled. 43 cycles of treatment have been given to these12 patients. Initial cohort of 3 patients at the 20 mg dose level had no dose limiting toxicity (DLT). At the 30 mg dose level 3/6 patients had DLT (thrombocytopenia grade 1: 2 pts; grade 3:1 pt; grade 4: 1 pt; and diarrhea grade 3: 1 pt. One pt at the 30 mg dose level has a confirmed partial response and remains on study after 6 cycles of treatment. Subsequent cohort of 3 patients had 1 dose DLT with doubling of the creatinine. The main DLT was thrombocytopenia in 3/6 pts at the 30 mg dose level. Conclusions: The recommended dose for phase II testing of LBH589 is 20 mg orally 3 times per week in combination with standard dose letrozole.

Oxaliplatin, Fludarabine, Cytarabine, and Rituximab Combination Therapy Induces High Response Rates in Agressive Chronic Lymphocytic Leukemia (CLL) and Richter's Syndrome (RS).

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3443-3443 ◽  
Author(s):  
Apostolia-Maria Tsimberidou ◽  
William Wierda ◽  
William Plunkett ◽  
Susan O'Brien ◽  
Thomas J. Kipps ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Level ◽  
Phase Ii ◽  
Research Funding ◽  
Response Rates ◽  
Off Label ◽  
Level 3 ◽  
Level 1 ◽  
Grade 3 ◽  
Level 2

Abstract Abstract 3443 Poster Board III-331 Introduction The first Phase I-II clinical trial of oxaliplatin, fluradabine, cytarabine (Ara-C), and rituximab (OFAR1) demonstrated significant activity in refractory CLL and RS (Tsimberidou et al, J Clin Oncol, 2008;26:196). To enhance the response rate and decrease myelosuppression, the dose of oxaliplatin was increased to 30mg daily, the dose of Ara-C was decreased to 0.5g/m2 daily and the optimal number of days of fluradabine and Ara-C administration was explored (OFAR2). Methods In a Phase I-II study of OFAR2, patients were treated with oxaliplatin 30mg/m2, D1-4; fludarabine 30mg/m2, Ara-C 0.5g/m2; rituximab 375mg/m2, D3; and pelfigrastim 6mg, D6. Fludarabine and Ara-C were given on D2-3 (dose level 1) D2-4 (dose level 2) or D2-5 (dose level 3); courses were repeated every 4 weeks. Patients received prophylaxis for tumor lysis, DNA viruses, and PCP. A “3+3” design was used and the planned number of patients in the Phase II was 90 (CLL, 60; RS, 30). Results Ninety-one patients (CLL, 67; RS, 24) have been treated to date: Phase I, 12 patients (by dose level: 1, n=3; 2, n=6; and 3, n=3). DLTs were noted in 2 of 3 patients on dose level 3 (G4 diarrhea, 1; G4 neutropenic sepsis, 1); thus, dose level 2 was the MTD. Seventy-nine patients (relapsed CLL, 58; RS, 19) have been treated in the Phase II portion of the study. Patient characteristics were as follows: age > 60 years, 65%; 17p deletion, 38%; 11q deletion, 13%; 13q deletion, 16%; trisomy 12, 21%; no findings, 12%; unmutated IgVH, 80%; ZAP70-positive, 75%; and CD38 ≥30%, 58%. Response in patients treated in the Phase II recommended dose is shown in Table (evaluable, 67). The overall response rates in patients with 17p and 11q deletions were 48% and 55%, respectively. The median survival duration was 21 months (CLL, 21 months; RS, 9.5 months). At 18 months, the survival rates in patients with 17p and 11q deletions were 66% and 76%, respectively. Twelve patients underwent stem cell transplantation after OFAR2 (as post-remission therapy, n=10; as salvage, n=2). Overall, 196 cycles were administered. Grade 3-4 neutropenia, thrombocytopenia, and anemia were noted in 63%, 72%, and 39% of patients and in 57%, 70%, and 25% of cycles and Grade 3-4 infections in 19% of patients. Conclusion Preliminary results demonstrated that OFAR2 induced response in 40% of patients with RS and 63% of patients with relapsed/refractory CLL. OFAR2 had antileukemic activity in patients with 17p deletion. Clinical outcomes appeared to be superior to those of OFAR1 in refractory CLL, whereas results of OFAR1 appeared to be superior to those of OFAR2 in RS. Accrual is ongoing. Disclosures Tsimberidou: ASCO: ASCO Career Development Award; Sanofi: Research Funding. Off Label Use: Oxaliplatin is used off-label. Wierda:Genentech: Honoraria; Bayer, Sanofi-Aventis, Abbott, GSK: Research Funding; GSK, Trubion, Ligand, Genentech, Medimmune, Abbot: Consultancy; Celgene: Speakers Bureau. Plunkett:Sanofi-Aventis: Research Funding. O'Brien:Genentech: Research Funding; Sanofi: Consultancy. Kipps:NCI: Grant P01CA-81534.

A Phase I Study of Idarubicin Dose Escalation for Remission Induction Therapy in Acute Myeloid Leukemia

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1344-1344
Author(s):  
Mark Lee ◽  
Sung-Yong Kim
Keyword(s):  
Acute Myeloid Leukemia ◽  
Platelet Count ◽  
Phase I ◽  
Dose Level ◽  
Induction Therapy ◽  
Myeloid Leukemia ◽  
Phase I Study ◽  
Level 1 ◽  
Level 2 ◽  
Acute Myeloid

Abstract The maximum tolerated dose (MTD) of idarubicin has been acknowledged to be 12-15 mg/m2/day for 3 days for acute leukemias. Its MTD should be reevaluated in the treatment of acute myeloid leukemia (AML) in the era of granulocyte colony-stimulating factor and better supportive care. We conducted a phase I study to investigate the safety of escalating doses of idarubicin in combination with cytarabine 100 mg/m2/day for 7 days for previously untreated AML. The starting dose of idarubicin was 12 mg/m2/day for 3 days with dose escalations by 3 mg/m2/day. Cohorts of three patients were treated at each dose level, and the idarubicin dose was escalated up to 18 mg/m2/day until at least two patients among a cohort of three to six patients experienced the dose-limiting toxicities (DLTs) (traditional 3+3 design for phase I clinical trials: J Natl Cancer Inst 2009;101:708). Hematologic DLTs were defined as the time to recovery of neutrophils {absolute neutrophil count (ANC) ≥500/μL} or platelets (platelet count ≥20,000/μL) exceeded 42 days after the start of induction therapy (J Clin Oncol 2004;22:4290). Non-hematologic DLTs were defined as grade 4 or 5 toxicities (Leukemia 1998;12:865). We adopted the NCI CTCAE v3.0 to grade the hematologic and non-hematologic toxicities. Thirteen adult patients were enrolled in the study, but two and two were excluded at level 1 and level 2, respectively, because they received reinduction therapy for resistant disease within 4 weeks after the start of the assigned induction therapy. Consequently, nine patients were evaluable for the phase I study. The median times to recovery of neutrophils (ANC ≥500/μL) after the start of induction therapy at level 1, level 2, and level 3 were day 20 (range, 19-22), day 19 (range, 17-20), and day 25 (range, 21-26), respectively. The median times to recovery of platelet (platelet count ≥20,000/μL) at each level were day 20 (range, 19-23), day 20 (range, 16-34), and day 24 (range, 20-35), respectively. Therefore, grade 4 hematologic toxicities were observed at all 3 levels; however, these hematologic toxicities did not meet the criteria of the hematologic DLTs as defined in this study. There was any instance of grade 4 non-hematologic toxicity at each dose level. No death associated with the induction treatment was observed in this trial. Hematologic and non-hematologic DLTs as defined above were not observed at all 3 dose levels; therefore, idarubicin 18 mg/m2/day for 3 days could be defined as the MTD for this trial. Disclosures No relevant conflicts of interest to declare.

A phase I study of tirapazamine in combination with radiation and weekly cisplatin in patients with locally advanced cervical cancer

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 5543-5543
Author(s):  
D. Rischin ◽  
K. Narayan ◽  
A. Oza ◽  
L. Mileshkin ◽  
D. Bernshaw ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Pulmonary Embolism ◽  
Phase I ◽  
Dose Level ◽  
Phase I Study ◽  
Locally Advanced ◽  
Advanced Cervical Cancer ◽  
Locally Advanced Cervical Cancer ◽  
Level 1 ◽  
Grade 3

5543 Background and Purpose: Hypoxia is an adverse prognostic factor in locoregionally advanced cervical cancer treated with radiation. GOG are currently studying the hypoxic cytotoxin, tirapazamine (TPZ) in combination with biweekly intermediate dose cisplatin (CIS) and radiation in a large phase III trial. The aim of this phase I study was to develop a better tolerated regimen that added TPZ to the standard regimen of radiation and weekly low dose CIS. Methods: Eligible patients had previously untreated carcinoma of the cervix, Stages IB2 - IVA. The starting schedule was radiotherapy (45 to 50.4 Gy external beam radiation followed by brachytherapy), with concomitant weekly CIS 40 mg/m2 weeks 1–6 and weekly TPZ 290 mg/m2 (prior to CIS) in weeks 1–5. Results: Between 3/05 and 7/06 eleven patients were enrolled, median age (range) 52 (31–65), squamous cell carcinoma 10, adenocarcinoma 1, 1B2–5, IIA-1, IIB-3, IIIB- 1, IVA-1. The first 2 patients on dose level 1 experienced a dose limiting toxicity (DLT), one grade 3 ALT (SGPT) elevation and grade 4 pulmonary embolism and one grade 3 ototoxicity. Doses were decreased to dose level -1 CIS 30 mg/m2 and TPZ 260 mg/m2. Three patients were treated without any DLTs. Six patients were then treated on dose level -1a, CIS 35 mg/m2 and TPZ 260 mg/m2, with 2 DLTs: grade 3 neutropenia with dose omission and grade 4 pulmonary embolism with major hemodynamic compromise. The sixth patient on dose level -1a withdrew from the trial in week 2 after being advised about the DLTs observed on this dose level. 3 additional patients will be accrued on dose level -1 to confirm safety of this dose level. One patient has relapsed in pelvic nodes, all other patients remain disease-free with a median followup of 10 months (range 5 - 21) Conclusions: The combination of weekly TPZ and CIS with radiation for locally advanced cervical cancer was associated with more toxicity than anticipated with the recommended dose level being TPZ 260 mg/m2, CIS 30 mg/m2. No significant financial relationships to disclose.

Phase I study of biweekly intravenous paclitaxel plus intraperitoneal cisplatin and paclitaxel for gastric cancer with peritoneal metastasis.

2011 ◽  
Vol 29 (4_suppl) ◽  
pp. 139-139
Author(s):  
H. Ishigami ◽  
J. Kitayama ◽  
S. Kaisaki ◽  
H. Yamaguchi ◽  
H. Yamashita ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Phase I ◽  
Cancer Patients ◽  
Dose Level ◽  
Peritoneal Metastasis ◽  
Phase I Study ◽  
Level 1 ◽  
Grade 3 ◽  
Gastric Cancer Patients ◽  
Experienced Grade

139 Background: Intraperitoneal (IP) chemotherapy is promising for the treatment of gastric cancer with peritoneal metastasis. We previously verified the safety and efficacy of IP paclitaxel (PTX) combined with S-1 and intravenous (IV) PTX in phase I and phase II studies (Oncology. 2009; Ann Oncol. 2010). Secondly, we developed a new IP-containing chemotherapy regimen, IV PTX plus IP cisplatin (CDDP) and PTX, for patients who have failed S-1-based chemotherapy. We performed a phase I study to determine the maximum-tolerated dose (MTD) and recommended dose (RD) in gastric cancer patients. Methods: A total of 9 gastric cancer patients were enrolled who had shown progression of peritoneal metastasis after S-1-based chemotherapy. PTX was administered intravenously at a dose of 100 mg/m2 and intraperitoneally over 1 hour with an initial dose of 20 mg/m2 (level 1), stepped up to 30 or 40 mg/m2 depending on observed toxicity. CDDP was subsequently administered intraperitoneally at a dose of 30 mg/m2 over 24 hours after PTX infusion. PTX and CDDP were administered on days 1 and 15 in 4-week cycles. Results: At dose level 1, dose-limiting toxicities (DLTs) were observed in 2 of 3 patients. One patient experienced grade 4 leukopenia, and the other grade 3 vomiting. Because of higher toxicities than anticipated, the initial dose-escalation schedule was abandoned, and the doses of IV PTX and IP CDDP were reduced to 80 mg/m2 and 25 mg/m2, respectively, while keeping the dose of IP PTX at 20 mg/m2 (level 0). At dose level 0, one of the first 3 patients experienced grade 3 nausea, and an additional 3 patients experienced no DLTs. Consequently, the MTD and RD were determined to be dose level 1 and dose level 0, respectively. No patients experienced complications related to the peritoneal access device or IP infusion. Conclusions: Combination chemotherapy of IV PTX plus IP CDDP and PTX was shown to be a safe regimen that should be further explored in clinical trials. No significant financial relationships to disclose.

A dose-finding study for irinotecan, cisplatin, and S-1 (IPS) in patients with advanced gastric cancer (OGSG 1106).

2019 ◽  
Vol 37 (4_suppl) ◽  
pp. 144-144
Author(s):  
Hiroki Yukami ◽  
Masahiro Goto ◽  
Takayuki Kii ◽  
Tetsuji Terazawa ◽  
Toshifumi Yamaguchi ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Antitumor Activity ◽  
Febrile Neutropenia ◽  
Phase I ◽  
Advanced Gastric Cancer ◽  
Phase I Study ◽  
Fixed Dose ◽  
Level 1 ◽  
Grade 3 ◽  
Level 2

144 Background: In Japan, S-1 plus cisplatin is regarded as one of the standard first line treatment of advanced gastric cancer (AGC). However, the prognosis of AGC remains dismal. The development of more effective chemotherapeutic regimen is thus warranted. A combination of irinotecan, cisplatin, and S-1 (IPS) can be a promising triplet therapy for advanced gastric cancer. We conducted a phase I study of IPS to determine the dose-limiting toxicity (DLT), maximum-tolerated dose (MTD) and recommended dose (RD), and to assess its safety and antitumor activity in patients with AGC. Methods: This phase I study was designed and conducted in a 3 + 3 manner to determine the recommended dose (RD) of IPS for the subsequent phase II study. Patients received an escalating dose of intravenous irinotecan (level 1: 100/level 2: 125/level 3: 150 mg/m²) on day 1, a fixed dose of intravenous cisplatin (60 mg/m²) on day 1, a fixed dose of S-1 (80 mg/m² b.i.d.) orally on days 1-14, every 4 weeks. Results: Twelve patients were enrolled between June 2013 and February 2017. During the first cycle, one of the six patients in level 1 and two of six patients in level 2 developed the DLT (grade 4 leucocytopenia and grade 3 febrile neutropenia). The MTD of irinotecan was 125 mg/m 2 (level 2) and the RD of irinotecan was considered to be 100 mg/m² (level 1). The most common grade 3 or 4 adverse events included neutropenia 75 % (9/12), anemia 25% (3/12), anorexia 8% (1/12), and febrile neutropenia 17% (2/12). Among six patients with measurable lesions, the response rate was 66.7% (4/6) [95% CI, 33.3-90.7%]. Two patients were performed R0 resection after IPS, with one patient achieved pathological complete response. The median survival time is under analysis. Conclusions: RD of IPS was determined to be 100 mg/m² of irinotecan, 60 mg/m² of cisplatin, and 80 mg/m² of S-1. Our data showed that this regimen provided acceptable antitumor activity and a favorable toxicity profile. Further evaluation of this regimen is warranted. Clinical trial information: UMIN000006864.

Phase I dose-finding study of sorafenib in combination with capecitabine and cisplatin as a first-line treatment in patients with advanced gastric cancer

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 4559-4559
Author(s):  
C. Kim ◽  
J. Lee ◽  
Y. Choi ◽  
B. Kang ◽  
M. Ryu ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Phase I ◽  
Dose Level ◽  
Dose Finding ◽  
Finding Study ◽  
Level 3 ◽  
Dose Finding Study ◽  
Level 1 ◽  
Grade 3 ◽  
Level 2

4559 Background: We conducted a phase I dose-finding study of sorafenib (S) in combination with capecitabine (X) and cisplatin (P) in patients with previously untreated metastatic or inoperable advanced gastric cancer. Methods: Four dose levels of S, X, and P combination were tested. The doses of S (p.o. daily), X (p.o. on days 1–14), and P (i.v. on day 1) were escalated at the following schedule; level 1: S 400 mg/d, X 1,600 mg/m2/d, P 80 mg/m2; level 2: S 800 mg/d, X 1,600 mg/m2/d, P 80 mg/m2; level 3: S 800 mg/d, X 2,000 mg/m2/d, P 80 mg/m2; level 1A: S 800 mg/d, X 1,600 mg/m2/d, P 60 mg/m2. The cycle was repeated every 3 weeks. Dose limiting toxicities (DLTs) were evaluated only in the first cycles and a standard 3+3 dose escalation design was implemented. Results: A total 21 pts were enrolled in the study. No DLTs were observed at dose level 1 (n=3). One DLT (grade 3 diarrhea) was noted at dose level 2 (n=6), and 2 DLTs (two grade 4 neutropenias longer than 5 days in duration) were observed at dose level 3 (n=6), which made the level 3 dose the maximum tolerated dose (MTD). However, at cycle 2 and thereafter at dose level 2, the relative dose intensity (RDI) of S and X could not be maintained (mostly below 80%) due to the frequent dose reductions and cycle delays. So, we explored a new dose level (1A) between dose level 1 and 2. Since no DLTs were found in 6 patients at level 1A with RDI mostly above 80% throughout the treatment period, level 1A was determined as recommended dose (RD). Most frequent grade 3 and 4 hematologic toxicities were neutropenia (25.0% of cycles), and most frequent grade 2 and 3 non-hematologic toxicities were hand-foot syndrome (9.4%), asthenia (7.0%), and anorexia (5.5%). The objective responses were confirmed in 10 out of 16 patients with measurable lesions (62.5%; 95% CI, 38.8–86.2%). With a median follow-up of 8.1 months, estimated median progression-free survival was 10.0 months (95% CI, 1.6–18.4 months) and median overall survival has not been reached. Conclusions: Diarrhea and neutropenia were DLTs in this S, X, and P combination. The dose schedule of sorafenib 400 mg po bid daily with capecitabine 800 mg/m2 po bid on days 1–14, and cisplatin 60 mg/m2 iv on day 1 in every 3 weeks is recommended for further development in AGC. [Table: see text]

A Phase I/II Study of Lenalidomide (R) with Low Dose Dexamethasone (d) and Cyclophosphamide (C) for Patients with Primary Systemic (AL) Amyloidosis.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 428-428 ◽  
Author(s):  
Efstathios Kastritis ◽  
Maria Roussou ◽  
Magdalini Migkou ◽  
Konstantinos Pamboukas ◽  
Maria Gavriatopoulou ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Level ◽  
Phase Ii ◽  
Low Dose ◽  
Alkylating Agents ◽  
Al Amyloidosis ◽  
Hematologic Response ◽  
Level 1 ◽  
Grade 3 ◽  
Level 2

Abstract Abstract 428 Lenalidomide (R) has significant activity in patients with multiple myeloma (MM). R has also shown activity in patients with AL amyloidosis, especially in combination with dexamethasone (D). However, AL patients are usually frail and R at the standard dose of 25 mg/day has been associated with significant toxicity. In MM patients, R with low dose D (Rd) has a better toxicity profile than the combination of R with high dose D. Alkylating agents, such as cyclophosphamide (C), are active in patients with AL and combinations of R with alkylating agents have given promising results in patients with MM. Thus, we designed a phase I/II trial of R, with low dose D and low dose C (RdC) in patients with AL. Primary objective of the study was to determine the maximum tolerated dose (MTD) for RdC and to assess hematologic response. Patients receive D 20 mg on days 1-4 (total 80 mg per cycle) , C on days 1-10, R on days 1-21 every 28 days, according to dose level (level 0: R 10 mg, C 50 mg, level 1: R 10 mg, C 100 mg, level 2: R 15 mg, C 100 mg). In the phase I part of the study, patients were observed for 2 cycles for determination of Dose Limiting Toxicity (DLT) according to a standard 3+3 design. Patients with a creatinine ≤2.5 mg/dL and adequate hepatic function were enrolled. All patients receive low-dose aspirin or LMWH if indicated. So far 23 patients have been enrolled in the study (16 in phase I, 7 in phase II). In the phase I study, 3 patients were enrolled in dose level 0, 7 in dose level 1 and 6 in dose level 2. Dose level 2, (R 15 mg, C 100 mg) is being further explored; 7 patients have been enrolled in phase II and accrual is ongoing. So far, 132 cycles of therapy have been administered; 8 patients have receive ≥6 cycles of RdC and 3 have completed 12 cycles of treatment. According to consensus criteria, heart was involved in 65%, kidneys in 61%, liver in 9% and 17% had AL-related peripheral neuropathy; 95% of the patients were Mayo stage II or III. Most patients (70%) were previously untreated. Among 7 pretreated patients, 2 had refractory disease, 2 had prior thalidomide and 5 had prior bortezomib. Hematologic response rates for patients who received at least 2 cycles of treatment, among all cohorts, was 64% and for the patients treated at dose level 2 was 75%. Median time to hematologic response was 2.5 months (range 0.9-4.8 months) for all patients and 1 month (range 0.9-2.9) for those treated at dose level 2. Organ responses have been recorded in 5 patients so far (3 cardiac and 3 renal responses, 1 patient had both cardiac and renal response). After a median follow-up of 7 months, 7 patients have died; 5 due to progressive heart amyloid, one patient had an acute MI followed by acute stent thrombosis and one died due to sepsis. The most common hematologic toxicities were anemia (grade 3/4 in 17%) and neutropenia (grade 3/4 in 17%). Most common non-hematologic toxicities were infection (grade ≥3 in 22%), fatigue (grade ≥3 in 9%), and rash (in 22%, grade 3 in 4%); also one patient suffered a stroke and one had DVT while on treatment with RdC. In parallel, and on a compassionate basis, AL patients with creatinine >2.5 mg/dL or on dialysis, were offered RdC with R dose adjusted according to CrCl. Initially R was given 15 mg every other day for CrCl <30 ml/min, or 15 mg thrice per week on the day after dialysis but due to toxicity R dose was reduced to 10 mg. So far, 13 patients have been treated with attenuated-dose RdC: 3 patients achieved a CR, one achieved a cardiac and one patient a liver response. However, the non-hematologic toxicity of the combination in patients with renal impairment was significant including fatigue (53%), infections (38%), rash (31%), diarrhea (15%), hyponatriemia (15%). Three patients discontinued treatment due to toxicity after the 1st cycle (including one early death due to non-neutropenic infection). In conclusion, RdC is an effective oral regimen for patients with AL amyloidosis, inducing significant rates of hematologic and organ responses. The recommended dose for RdC was R at dose of 15 mg, C at a dose of 100 mg and 20 mg of D and is further evaluated in the phase II of the study. Toxicity is manageable for patients with serum creatinine <2.5 mg/dL but can be significant for AL patients with more severe renal impairment. Lower doses of R, at 10 mg or less every other day or thrice per week should be used in these patients. Accrual in the phase II study is ongoing and updated results will be presented at the meeting. Disclosures: Dimopoulos: Celgene: Honoraria, Research Funding.

A Phase I Study of Lenalidomide in Combination with Fludarabine-Rituximab in Previously Untreated CLL/SLL.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3426-3426
Author(s):  
Jennifer R Brown ◽  
Jeremy S. Abramson ◽  
Ephraim P. Hochberg ◽  
Evgeny Mikler ◽  
Virginia Dalton ◽  
...  
Keyword(s):  
Phase I ◽  
Immune Function ◽  
Dose Level ◽  
Phase I Study ◽  
Objective Response ◽  
Study Entry ◽  
Hematologic Toxicity ◽  
Significant Difference ◽  
Level 1 ◽  
Grade 3

Abstract Abstract 3426 Poster Board III-314 Lenalidomide is an immunomodulatory drug recently reported to have an objective response rate (ORR) of 35-53% in relapsed/refractory CLL, even with poor risk features. Initial therapy of CLL currently includes chemoimmunotherapy combinations like FCR, which have high response rates and improved PFS, but at the cost of myelosuppression and infection. Given the high ORR reported with lenalidomide and its potential to spare immune function, we undertook this Phase I study to explore the safety and tolerability of lenalidomide in combination with fludarabine and rituximab. Eligibility criteria included a confirmed diagnosis of CLL/SLL, previously untreated with systemic therapy with an indication for therapy by NCI-WG 1996 criteria; ANC > 1000, platelets > 50K, and adequate organ function. Six dose levels were planned, beginning with fludarabine 25 mg/m2 days 1-3, rituximab 375 mg/m2 day 1, and lenalidomide 2.5 mg administered on days 1-21 of a 28-day cycle. The study used a standard 3+3 dose escalation design, with dose limiting toxicity (DLT) assessed in the first 28 days and defined as grade 3 or greater non-hematologic toxicity, grade 4 neutropenia or thrombocytopenia, grade 3 febrile neutropenia, or a >2-week delay in initiating the second cycle. Nine patients were enrolled on this study, 7 males and 2 females, with a median age of 59 yrs (range 37-66). The median time from diagnosis to study entry was 66.1 months (range 11.7-82.8 months). The median WBC at study entry was 99.6 (range 11.1-325.7). Six patients had Rai 3-4 disease, and three patients had bulky lymphadenopathy (>5 cm) on physical exam. Median beta-2 microglobulin level at study entry was 3.8 mg/L (range 2.5-7.7). The first cohort enrolled four patients, of whom two developed DLTs (grade 4 neutropenia persisting through day 50; febrile syndrome with grade 3 rash, myalgias and grade 4 CPK elevation). The study then proceeded to enroll five patients at dose level -1, with the same dosing of rituximab and fludarabine, but reduced lenalidomide dosing of 2.5 mg every other day for 21 of 28 days. Only two of five patients on dose level -1 completed the planned six cycles of therapy. The other three patients discontinued after 3 cycles due to toxicity: persistent grade 2 thrombocytopenia preventing further therapy; recurrent grade 3-4 neutropenia and thrombocytopenia, despite growth factor support, dose reduction and holding lenalidomide; and intermittent recurrent grade 3 tumor flare, rash and hand-foot syndrome, along with recurrent grade 3 neutropenia despite similar measures as above. At that point the study was closed to enrollment due to the significant myelotoxicity and idiosyncratic tumor flare, resulting in only two of nine patients completing the planned therapy. The median number of cycles completed for all patients was three. Six of the nine enrolled patients were evaluable for response, with five of nine having objective responses (56%, 90% CI 25-83%). No significant difference was observed in IgG and IgM levels between baseline and two months on study, although a trend toward a decrease in IgA levels (p=0.05) was observed. Baseline CD4 counts were variable (median 1139, range 529-2687), but showed significant declines of 574 cells by week 4 (p=0.003) and 707 cells by post-treatment (p=0.002). Analysis of alterations in serum cytokines is ongoing. We conclude that administering lenalidomide concurrently with fludarabine and rituximab is difficult, does not appear to preserve immune function, and limits the ability to deliver adequate therapy with either drug. Other trials currently in progress are exploring alternative schedules of lenalidomide administration with fludarabine and other standard CLL chemotherapy regimens; our data would favor a sequential schedule. Disclosures Brown: Celgene: Honoraria, Provided funding for this investigator-initiated study; Genzyme: Research Funding; Genentech: Consultancy; Calistoga: Consultancy. Off Label Use: Lenalidomide for CLL. Hochberg:Enzon: Speakers Bureau; Biogen-Idec: Speakers Bureau; Genentech: Speakers Bureau; Amgen: Speakers Bureau.

Sign in / Sign up

Export Citation Format

Share Document