Phase I/II Study of Volasertib (BI 6727), An Intravenous Polo-Like Kinase (Plk) Inhibitor, in Patients with Acute Myeloid Leukemia (AML): Updated Results of the Dose Finding Phase I Part for Volasertib in Combination with Low-Dose Cytarabine (LD-Ara-C) and As Monotherapy in Relapsed/Refractory AML

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1549-1549 ◽  
Author(s):  
Gesine Bug ◽  
Carsten Müller-Tidow ◽  
Richard F Schlenk ◽  
Alwin Krämer ◽  
Michael Lübbert ◽  
...  
Keyword(s):  
Complete Remission ◽  
Phase I ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Research Funding ◽  
Median Number ◽  
Salvage Treatment ◽  
Antileukemic Activity ◽  
Best Response ◽  
Grade 3

Abstract Abstract 1549 Background: The prognosis of patients (pts) with relapsed or refractory (rel/ref) AML who are considered unlikely to benefit from or tolerate intensive salvage treatment is unfavorable and novel treatment strategies are needed. Repeated cycles of LD-Ara-C are a therapeutic option for palliative treatment; however, the outlook for these pts remains unsatisfactory. Plks are critical in cellular division and mitotic progression and Plk1 is overexpressed in many cancers including AML. Volasertib is a first in class, selective and potent cell cycle kinase inhibitor that induces mitotic arrest and apoptosis by targeting Plk. In phase I/II trials in pts with solid tumors, volasertib demonstrated a favorable safety profile and encouraging antitumor activity. Here, we present updated results from the phase I part of an ongoing phase I/II study of volasertib in combination with LD-Ara-C or as monotherapy in AML pts considered ineligible for intensive salvage treatment. Material and Methods: This study follows a two-stage design. The phase I part, reported here, investigates the maximum tolerated dose (MTD) of volasertib as a 1-hr intravenous infusion on days 1 and 15 Q4W as monotherapy or in combination with fixed dose LD-Ara-C 20 mg bid subcutaneously on days 1–10 Q4W in pts with rel/ref AML. Dose escalation follows a 3+3 design with de-escalation. Blood samples for pharmacokinetic (PK) analyses were taken in cycles 1 and 2 and concentrations of volasertib and LD-Ara-C were determined. Results: In the monotherapy arm, increasing volasertib doses (150, 200, 350, 400, 450 mg) were evaluated in 29 pts (median age: 71 yrs [range 26–84]). Drug-related adverse events (AEs) were reported in 8 pts (27.6 %). Most frequent drug-related AEs (>5%) were anemia in 3 pts (10.3%), and thrombocytopenia, epistaxis, and nausea in 2 pts each (6.9%). Grade 3/4 drug-related AEs included thrombocytopenia (2 cases), anemia, diarrhea, mucositis, neutropenia, and pneumonia (1 case each); there was 1 fatal (grade 5) drug-related AE (fungal pneumonia). Of the drug-related AEs, the following were dose-limiting toxicities (DLTs) per protocol: grade 4 pneumonia and fatal fungal pneumonia (n=1, at 150 mg), and grade 3 mucositis (n=1, at 400 mg). Monotherapy dose escalation is ongoing; pts have received volasertib doses of 500 mg without having reached the MTD. Preliminary best response data indicated minor antileukemic activity at low doses (150 and 200 mg); with 4/13 pts achieving no change as best response, mostly of short duration (median number of cycles initiated: 1 [range 1–5]). At higher monotherapy doses (≥350 mg), antileukemic activity was observed with 4/16 pts achieving a complete remission with incomplete blood count recovery (CRi) and 5/16 having temporarily stable blood values as best response. In the combination arm, volasertib doses of 150–400 mg were investigated. The MTD for volasertib in combination with LD-Ara-C was 350 mg (Bug et al ASH 2010). Seven out of 32 pts treated with volasertib + LD-Ara-C achieved a complete remission (CR or CRi). In responding patients, a median number of 6 treatment cycles was initiated (range 3–13) and a preliminary analysis revealed a median overall survival of 551 days (range 165–595). PK analysis showed that volasertib is a moderate clearance drug with multi-compartmental PK behavior with a large volume of distribution (>4000 L) and a long terminal half-life (∼111 hrs). No drug interaction after co-administration of LD-Ara-C was observed. Conclusions: The phase I part of the study determined the MTD of volasertib in combination with LD-Ara-C to be 350 mg; the MTD of volasertib monotherapy has not yet been determined. Volasertib was well tolerated in this heavily pretreated AML pt population at doses above the recommended phase II volasertib dose used in pts with solid tumors. Most of the reported higher grade drug-related AEs were due to the myelosuppressive effect of volasertib. Preliminary results from the phase I trial show antileukemic activity of volasertib as monotherapy and in combination with LD-Ara-C. These results indicate Plk to be a potential new target for AML treatment and warrant proceeding with further clinical investigation of volasertib in AML pts. Disclosures: Bug: Novartis Pharma GmbH: Consultancy, Honoraria; Celgene GmbH: Consultancy, Honoraria. Off Label Use: Volasertib is an investigational agent. Müller-Tidow:Boehringer Ingelheim: Research Funding. Krug:Boehringer Ingelheim: Research Funding. Voss:Boehringer Ingelheim: Employment. Taube:Boehringer Ingelheim: Employment. Fritsch:Boehringer Ingelheim: Employment. Garin-Chesa:Boehringer Ingelheim: Employment. Ottmann:Boehringer Ingelheim: Consultancy. Döhner:Celgene, Clavis: Membership on an entity's Board of Directors or advisory committees.

Low-dose metronomic topotecan and pazopanib in children with recurrent or refractory solid tumors: A C17 Canadian phase I trial (TOPAZ).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 10020-10020
Author(s):  
Arif Manji ◽  
Daniel A. Morgenstern ◽  
Yvan Samson ◽  
Rebecca Deyell ◽  
Donna Johnston ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Stable Disease ◽  
Low Dose ◽  
Pediatric Patients ◽  
Novel Approach ◽  
Best Response ◽  
Grade 3 ◽  
Relapsed Disease

10020 Background: Low-dose metronomic topotecan (mTP) represents a novel approach to chemotherapy delivery which, in preclinical models, may work synergistically with pazopanib (PZ) in targeting angiogenesis. This study was designed to determine the recommended phase 2 dose (RP2D) of mTP/PZ in pediatric patients with solid tumors, while describing the safety and toxicity of this regimen. Methods: A phase I dose-escalation, pharmacokinetic (PK) and pharmacodynamic (PD) study of mTP/PZ was conducted at ten sites across Canada, enrolling pediatric patients aged 2-21 years with relapsed/refractory solid tumors. Patients were treated with oral mTP and PZ suspension daily without interruption in 28-day cycles, with dose escalation in accordance with the rolling-six design. Five dose levels (0.12/125, 0.16/125, 0.22/125, 0.22/160, and 0.3/160 mg/m2/day of mTP/PZ) were evaluated. PK studies were performed on day 1 and at steady state, and PD studies included circulating angiogenic factors VEGFR1, VEGFR2, VEGF, endoglin and placental growth factor. Results: Thirty patients (pts) were enrolled, of whom 26 were evaluable for dose-limiting toxicity (DLT), with median age 12 years (3-20). The most common diagnoses included osteosarcoma (8), neuroblastoma (NB, 7), Ewing sarcoma/PNET (4), and rhabdomyosarcoma (4). The most common grade 3/4 adverse events (AEs) related to protocol therapy were neutropenia (18%), thrombocytopenia (11%), lymphocytopenia (11%), AST elevation (11%), and lipase elevation (11%). Only 2 cycle-1 DLTs were observed on study, both at the 0.3/160 mg/m2 mTP/PZ dose level (2/5 pts) comprising persistent grade 3 thrombocytopenia and grade 3 ALT elevation. No AEs experienced beyond cycle-1 required treatment discontinuation. Best response was stable disease in 10/25 pts (40%) for a median duration of 6.4 months (1.7-45.1). One patient with refractory NB achieved stable disease for 45 months and continued on mTP/PZ via compassionate access after study closure. PK and PD results are pending at this time. Conclusions: The combination of oral mTP and PZ is safe and tolerable in pediatric patients with solid tumors, with a RP2D of mTP 0.22 mg/m2/day and PZ suspension 160 mg/m2/day. Ten patients achieved stable disease for a median of 6 months. The lack of objective responses suggests that this combination is likely of limited benefit for relapsed disease, but may play a role as maintenance therapy. Clinical trial information: NCT02303028.

scholarly journals Phase I clinical trial of the combination of eribulin and everolimus in patients with metastatic triple-negative breast cancer

2019 ◽  
Vol 21 (1) ◽  
Author(s):  
Jin Sun Lee ◽  
Susan E. Yost ◽  
Suzette Blanchard ◽  
Daniel Schmolze ◽  
Hongwei Holly Yin ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Phase I ◽  
Dose Level ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Median Number ◽  
Primary Objective ◽  
Best Response ◽  
Grade 3 ◽  
Number Of Cycles

Abstract Background Alteration of the PI3K/AKT/mTOR pathway is a common genomic abnormality detected in triple-negative breast cancer (TNBC). Everolimus acts synergistically with eribulin in TNBC cell lines and xenograft models. This phase I trial was designed to test the safety and tolerability of combining eribulin and everolimus in patients with metastatic TNBC. Methods The primary objective of this study was to evaluate the safety and toxicities of the combination. Patients with metastatic TNBC who had up to four lines of prior chemotherapies were enrolled. The combination of eribulin and everolimus was tested using three dosing levels: A1 (everolimus 5 mg daily; eribulin 1.4 mg/m2 days 1 and 8 every 3 weeks), A2 (everolimus 7.5 mg daily; eribulin 1.4 mg/m2, days 1 and 8 every 3 weeks), and B1 (everolimus 5 mg daily; eribulin 1.1 mg/m2 days 1 and 8 every 3 weeks). Results Twenty-seven patients with median age 55 years were enrolled. Among 8 evaluable patients who received dose level A1, 4 had dose-limiting toxicities (DLTs). Among 3 evaluable patients treated with dose level A2, 2 had DLTs. Among 12 evaluable patients who received dose level B1, 4 had DLTs. The DLTs were neutropenia, stomatitis, and hyperglycemia. Over the study period, 59% had a ≥ grade 3 toxicity, 44% had ≥ grade 3 hematologic toxicities, and 22% had grade 4 hematologic toxicities. The most common hematological toxicities were neutropenia, leukopenia, and lymphopenia. Thirty-three percent had grade 3 non-hematologic toxicities. The most common non-hematological toxicities were stomatitis, hyperglycemia, and fatigue. The median number of cycles completed was 4 (range 0–8). Among 25 eligible patients, 9 patients (36%) achieved the best response as partial response, 9 (36%) had stable disease, and 7 (28%) had progression. The median time to progression was 2.6 months (95% CI [2.1, 4.0]), and median overall survival (OS) was 8.3 months (95% CI [5.5, undefined]). Conclusion Eribulin 1.1 mg/m2 days 1 and 8 every 3 weeks with everolimus 5 mg daily was defined as the highest dose with acceptable toxicity (RP2D). The combination is safe, and efficacy is modest. A post hoc analysis showed that participants that used dexamethasone mouthwash stayed on treatment for one additional cycle. Trial registration ClinicalTrials.gov, NCT02120469. Registered 18 April 2014

Clofarabine (CLO) Has Single Agent Activity in Relapsed and Refractory Non-Hodgkin Lymphoma (NHL) Including Rituximab (R)-Refractory Patients (pts).

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 921-921
Author(s):  
Chadi Nabhan ◽  
Jacob David Bitran ◽  
Walter Fried ◽  
Angel G. Galvez ◽  
Laura Magid ◽  
...  
Keyword(s):  
Stem Cell ◽  
T Cell ◽  
Stem Cell Transplantation ◽  
Phase I ◽  
Phase Ii ◽  
Research Funding ◽  
Large Cell ◽  
Median Number ◽  
Low Grade ◽  
Grade 3

Abstract Abstract 921 Background: CLO is a second generation nucleoside analogue with known activity in acute leukemia and myelodysplasia. As there is no standard therapy for refractory and transplant-ineligible relapsed NHL, and given the activity that purine analogues have in lymphoid malignancies, we sought to investigate the activity of CLO in this pt population regardless of histology. Methods: Eligible pts had measurable disease by CT and/or PET, ECOG performance status ≤ 2, and adequate renal, cardiac, liver, and bone marrow function (unless cytopenias were disease-related). CLO was given in the outpatient setting intravenously over 1-hour days 1-5 every 28 days for 6 cycles maximum. All pts received anti-viral and anti-pneumocystis jiroveci prophylaxis. First, we initiated a phase I portion using a standard 3×3 study design. CLO was given at 4 mg/m2 in cohort 1 with subsequent cohorts to be escalated by 2 mg/m2 each. Once the maximum tolerated dose (MTD) was determined, the phase II portion of this study was initiated at the MTD. All pts were followed until disease progression. Results: Thirty-three pts (18 females, 15 males) have been enrolled (7 in the phase I portion and 26 in the phase II), of which 29 are evaluable for response and/or toxicity (2 just started therapy, 1 taken off due to persistent cytopenias, and 1 withdrew consent). Median age was 69 years (range 27-88), median number of prior therapies was 3 (range 1-8), with 21% failing prior stem cell transplantation and 74% being R-refractory. Median time from original diagnosis to first CLO treatment was 36 months (range 6-216). Histologies included 12 diffuse large cell, 5 follicular, 5 small lymphocytic, 4 anaplastic large T-cell, and 1 each for Richter, mantle cell, marginal zone, peripheral T-cell, transformed, non-specific T-cell, and mixed histology. Median number of CLO cycles was 4 (range 1-6). Thrombocytopenia was the dose-limiting toxicity at 6 mg/m2 in 2/6 pts. The MTD recommended for phase II was 4 mg/m2. With a median follow up of 8 months (range 1-33), 7 pts (24%) showed complete response (CR) and 8 (27%) had partial response (PR) for an overall response rate of 51%. Four pts (13%) demonstrated stable disease and 10 (34%) showed progression. Median duration of response was 7 months (range 2-33+) with 6 pts continuing in remission including a patient who is undergoing stem cell transplantation. Median time to progression (TTP) was 3.5 months with median overall survival of 8 months. sEVEN pts (24%) remain progression-free. Of patients who were followed for more than 12 months, 60% were alive at 1-year. Five of the CR pts were of low-grade histology while only 2 had large cell lymphoma. All pts required growth factor support. Toxicity was mainly hematologic with 63% experiencing grade 3/4 thrombocytopenia, 60% grade 3/4 neutropenia, and 39% grade3/4 anemia, and 63%. Grade 3 and/or 4 non-hematologic toxicity included 2 (6%) with tumor lysis syndrome, 2 (6%) infectious episodes (pneumonia and bilateral cellulitis), 2 (6%) renal insufficiency, 2 (6%) fatigue, 1 (3%) seizure activity, 1 (3%) pleural effusion, and 1 hypokalemia (3%). No treatment-related mortality. Conclusions: CLO is active in heavily pre-treated B-cell NHL including R-refractory pts. Activity appears more pronounced in low-grade histology. The drug is well-tolerated and can be administered as an outpatient. Reversible myelosuppression is the major toxicity. Future studies in front-line in combination with R are warranted. Disclosures: Nabhan: Bayer: Honoraria, Research Funding, Speakers Bureau; Genzyme: Research Funding; Genentech: Honoraria, Speakers Bureau. Venugopal:Genzyme: Honoraria, Research Funding; Genentech: Honoraria, Research Funding, Speakers Bureau.

Phase I-II Trial of Oral Cyclophosphamide, Prednisone and Lenalidomide (Revlimid®) (CPR) for the Treatment of Patients with Relapsed and Refractory Multiple Myeloma

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3055-3055
Author(s):  
Donna E. Reece ◽  
Esther Masih-Khan ◽  
Arooj Khan ◽  
Saima Dean ◽  
Sharon Fung ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Dose Level ◽  
Research Funding ◽  
Response Rate ◽  
Objective Response ◽  
Median Number ◽  
Prior Therapy ◽  
Best Response ◽  
Level 3 ◽  
Grade 3

Abstract Abstract 3055 Lenalidomide (Revlimid®) and dexamethasone is an effective regimen for relapsed/refractory (rel/ref) multiple myeloma (MM) patients (pts) with an overall response rate of 60% and median time to progression of 13.4 months (Dimopoulos ME, et al. Leukemia 2009; 23: 2147-52). We combined lenalidomide with the alkylating agent combination of cyclophosphamide and prednisone—an older regimen with minimal cumulative myelosuppression and good activity as second or third line therapy (Trieu Y, et al, Mayo Clin Proc 2005; 80: 1582). The CPR regimen consisted of cyclophosphamide (CY) on days 1, 8, and 15, lenalidomide on days 1–21 and prednisone 100 mg q 2 days in a 28-day cycle. ASA 81 mg/day was given as DVT prophylaxis. Three dose levels were evaluated using a 3 × 3 dose escalation design. Thirty-two pts were entered between 11/2007-06/2009; median age was 64 (42-80) yrs, 60% were male, and immunoglobulin isotype was IgG in 19 (62%), IgA in 8 (25%) and light chain in 4 (13%) pts. Median β2-microglobulin level was 257 (92-767) nm/L, albumin 39 (34-48) g/L, creatinine 83 (50-126) μmol/L, platelet count 355 (75-479) × 109/L and ANC 2.5 (1.1-6.1) × 109/L. The median number of prior regimens was 2 (1-5). Prior therapy included: ASCT (single in 91%; double in 19%), thalidomide (28%) and bortezomib (50%). FISH cytogenetics were available in 13 pts; 1 had del 13q but none had t(4;14) or del p53. Table 1 summarizes protocol treatment delivered. Table 1. Dose level N Cyclophosphamide dose (mg/m2) Lenalidomide dose (mg) Prednisone dose (mg) Median # cycles given 1 3 150 15 100 12 (12–34+) 2 3 150 25 100 10 (9–23) 3 26 300 25 100 17 (5–28+) 1–3 (All) 32 150–300 15–25 100 19 (5–34+) Dose limiting toxicity was not observed during cycle 1 at any dose level. Grade 3–4 toxicities during the trial included: thrombocytopenia in 7 (22%) and neutropenia in 9 (29%), managed with dose reduction and/or growth factors; five episodes of febrile neutropenia occurred, all at dose level 3. In cohort 3, other grade 3–4 non-hematologic toxicities included 1 episode each of abdominal pain/bacteremia, hypokalemia, fatigue, sick sinus syndrome, cardiac amyloidosis, perforated diverticulum and 2 episodes of DVT. Two heavily pretreated pts developed 2° MDS, including 1 previously treated for lymphoma, 43 and 190 mos after the diagnosis of MM. The best response using modified EBMT criteria was documented at a median of 7 (1-26) cycles and included the following: dose level 1 (1 CR, 2 PR); dose level 2 (1 VGPR, 2 PR); dose level 3 (4 CR, 14 VGPR, 11 PR, 1 MR and 1 stable disease). At a median F/U of 16 (5-34) months, 13 pts remain on study and 18 have progressed at a median of 10 (2-23) mos; 1 was lost to F/U and 9 have died of progressive MM. The 1-year actuarial OS and PFS rates are 93% (95% CI 76–98%) and 78% (95% CI 60–89%), respectively. We conclude: 1) the combination of full doses of the agents in CPR can be given in a 28 day cycle with an acceptable safety profile; 2) the objective response rate (CR + PR + MR) in all 32 pts to date is 94%; 3) the 1-year OS of 93% and PFS of 78% compare favorably with other 3-drug combinations in rel/ref MM pts; 4) further evaluation of this regimen in newly diagnosed pts would be of interest. Disclosures: Reece: Celgene: Honoraria, Research Funding. Off Label Use: Combination of lenalidomide and cyclophosphamide and prednisone in relapsed and refractory myeloma patients. Chen:Celgene Corporation: Consultancy, Honoraria, Research Funding. Kukreti:Celgene: Honoraria.

A Phase I-II Study of the Efficacy and Safety of Lenalidomide (LEN) Combined to Azacitidine (AZA) in Higher Risk MDS and AML with Del 5q - a Study By the Groupe Francophone Des Myelodysplasies (GFM)

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2892-2892 ◽  
Author(s):  
Lionel Ades ◽  
Christian Récher ◽  
Julie Lejeune ◽  
Aspasia Stamatoullas ◽  
Marie Sebert ◽  
...  
Keyword(s):  
Phase I ◽  
Primary Endpoint ◽  
Research Funding ◽  
Response Rate ◽  
Early Death ◽  
Complete Response ◽  
Cytogenetic Response ◽  
Median Number ◽  
Intensive Chemotherapy ◽  
Best Response

Abstract Background: Higher risk MDS and AML with del(5q) carry very poor prognosis, but show some response to AZA and LEN as single agents (Adès Blood 2009, Itzykson, Blood 2010). The combination of LEN and AZA has been tested in non-del 5q MDS patients with encouraging results and limited toxicity (Sekeres, Blood 2012). Sequential combination of AZA and LEN has also shown to be feasible and potentially effective in 20 patients with higher-risk MDS with del(5q) in a phase I study (Platzbecker, Leukemia 2013). In this phase I-II trial, we combined escalating doses of LEN to AZA in higher risk MDS and AML with del(5q). Methods: Patients with IPSS int-2 or high MDS, CMML with WBC < 13,000/mm3 and marrow blasts > 10% and AML (20-30% marrow blasts) with 5q deletion with or without additional cytogenetic abnormalities could be included provided they had not previously received LEN or AZA. Patients should also have contra indication to intensive chemotherapy (IC), precluding inclusion in a GFM competing trial combining IC and LEN in higher risk MDS and AML with del 5q. In the present trial, patients received AZA (75 mg/m2 x5 d, every 28 days) combined with escalating doses of LEN (5 mg/d x14 d in cohort 1, 5 mg/d x21 d in cohort 2 and 10 mg/d x21 d in cohort 3). For patients in hematological CR, PR, HI or marrow CR (MDS) and CR or PR (AML) after cycle 2 or 4, treatment was to be continued at the same schedule unless unacceptable toxicity or overt progression occurred. The primary endpoint was response assessed according to IWG 2006 criteria. Secondary endpoints were best response over the 4 cycles and survival. Medians [IQR] are reported unless specified. Intent-to-treat analyses were made. Results: 49 patients were enrolled, including 15, 10 and 24 patients in cohort 1 (LEN 5 mg/d x14d), 2 (LEN 5 mg/d x21d) and 3 (LEN 10 mg/d x21d). 24 were males and the median age was 69 (63-74). According to WHO classification, 1 patient had CMML, 9 RAEB1, 22 RAEB2 and 17 AML. PS was 0, 1 and 2, in 30.8%, 43.6% and 25.6% patients, respectively. However, as said above, patients included in this trial were considered unfit for IC due to their age and/or comorbidities (cardiovascular in 30 patients, pulmonary e in 10, and neurological in 6 pts). Del(5q) was isolated in only 8.3% pts, while 85.4% had del (5q) and at least 2 additional abnormalities (i.e., complex).. IPSS was int-2 in 33% patients and high in 66% patients. Overall, 143 cycles were administered (median 2/patient, including 9 patients who received 6 or more cycles). In the three cohorts, the median number of cycles received was 2 (1-2), 2 (1-4.75) and 4 (2-5.5) respectively. Fifteen (30.6%) patients discontinued treatment before the second cycle, due to early death (n=9), adverse events (n=3), progression (n=2), or CNS hemorrhage (n=1). They were all considered as non responders (primary endpoint). After 2 cycles, 4 (8.2%) achieved CR, 4 (8.2%) marrow CR and 4 (8.2%) stable disease with hematological improvement (ORR= 24%). The best response rate over the 4 courses was 2/15 (13.3%) in cohort 1, 1/10 (10%) in cohort 2, and 9/24 (37.5%) in cohort 3 (ORR=24%). The response rate was 37.5% in patients receiving 10 mg/d, versus 12% in those receiving 5 mg (p=0.051) while other baseline parameters had no impact on response: IPSS (p=0.073), marrow blasts >10% (p=0.16), sex (p=0.74), cytogenetic complexity (p=0.26) or PS (p=0.419). 2/6 CR patients achieved cytogenetic complete response: 0/2 in cohort 1, 0/0 in cohort 2, and 2/4 in cohort 3. One year OS was estimated at 22.9% [95% IC: 12.3-42.5]. We failed to identified any prognostic factor associated with OS (IPSS (p=0.52), marrow blasts >10% (p=0.28), sex (p=0.99), isolated del(5q) (p=0.68), cohort (p=0.2) and PS (p=0.33)). Regarding toxicity, 58 SAEs (grade 3-4) were reported in 38 patients, including 35 infectious events, 7 bleding events, 3 deep venous thrombosis. Conclusion: In this elderly population of higher risk MDS or AML considered unfit for intensive chemotherapy, and with del 5q that was part of a complex karyotype in almost all cases, the combination of AZA with escalated doses of LEN was associated with early discontinuation (<4 cycles) in 30/49 (61.2%) of the patients, mostly due to progression or toxicity, and only 12/49 (24.5%) response. The fact that some responders also achieved cytogenetic response may however be encouraging. Disclosures Vey: Janssen: Honoraria; Celgene: Honoraria; Roche: Honoraria. Park:Hospira: Research Funding; Celgene: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding. Fenaux:Amgen: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Celgene Corporation: Honoraria, Research Funding; Janssen: Honoraria, Research Funding.

A Q7D phase I study of TPI 287, a novel taxane, in advanced malignancies: Imaging studies, pharmacokinetics (PK) and circulating tumor cell (CTC) quantitation

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 12008-12008 ◽  
Author(s):  
J. J. Hwang ◽  
J. L. Marshall ◽  
S. Malik ◽  
H. Chun ◽  
T. Ahmed ◽  
...  
Keyword(s):  
Tumor Cell ◽  
Phase I ◽  
Dose Escalation ◽  
Phase I Study ◽  
Circulating Tumor Cell ◽  
Median Number ◽  
Maximum Tolerated Dose ◽  
Advanced Malignancies ◽  
Tumor Measurements ◽  
Grade 3

12008 Background: Taxanes have demonstrated activity across a broad range of cancers, but resistance remains an issue. TPI 287 is a third generation taxane designed to overcome issues of resistance secondary to mdr and mutant tubulin. The purpose of this Phase I study was to determine the maximum tolerated dose and pharmacokinetics of IV TPI 287. Methods: Phase I study: TPI 287 is administered IV on days 1, 8, 15 of a 28 day cycle (Q7D) with at least 3 patients treated per dose escalation, in a typical phase I design. Dosing began at 7 mg/m2 and has advanced to the fifth cohort of patients, who are being treated at a dose of 85 mg/m2. Tumor response is assessed after every second cycle via imaging and tumor measurements. Samples are collected for PK analysis and circulating tumor cell (CTC) quantitation. Results: Sixteen pts have been enrolled (9 males, median years = 60.11; 7 females, median years = 50.71: median number of previous chemotherapies = 4). Diagnoses included colorectal (4), prostate (3), breast, kidney, cervical, brain, lung, osteosarcoma, basal cell, endometrial, ovarian cancers. Of 16 pts, 8 and 5 have completed 1, 2 cycles, respectively. Only one drug related grade 3 adverse event (hypersensitivity reaction) occurred, at 14 mg/m2. No other reported toxicities are related to TPI 287. PK and CTC studies are ongoing. Conclusions: These initial results show that TPI 287 is well tolerated at a dose up to 56 mg/m2 administered Q7D, and dose escalation continues. [Table: see text]

Phase I dose escalation study of the anti-IGF-1R monoclonal antibody CP-751,871 in patients with refractory solid tumors

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 3586-3586 ◽  
Author(s):  
P. Haluska ◽  
H. Shaw ◽  
G. N. Batzel ◽  
L. R. Molife ◽  
A. A. Adjei ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Phase I ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Receptor Internalization ◽  
Pharmacokinetic Analysis ◽  
Adrenocortical Cancer ◽  
Dose Escalation Study ◽  
Multiple Tumor ◽  
Grade 3

3586 Background: The insulin-like growth factor 1 receptor (IGF-IR), a tyrosine kinase, and its ligands (IGF-I & -2) are upregulated in many human tumors (e.g., breast, prostate, colon and non-small cell lung cancer) and enhance proliferative and prosurvival signaling. Inhibition of IGF-IR activation in tumor models suppresses tumor growth and increases tumor sensitivity to chemotherapy, supporting the development of agents targeting IGF-IR. CP-751,871 is a potent, highly specific, fully humanized, monoclonal antibody that inhibits IGF-IR autophosphorylation and induces receptor internalization. Methods: A Phase I dose escalation study was initiated to define the safety and tolerability, and to characterize the pharmacokinetic properties of CP-751,871 in patients with advanced solid tumors refractory to standard therapies. Results: Following informed consent and screening, a total of 24 patients with refractory solid tumors (e.g. colorectal, NSCLC, sarcoma and prostate cancer; 1–6 previous regimens) were enrolled. Patients received 3 to 20 mg/kg of CP-751,871 by IV infusion on Day 1 of 3-week cycles in four dose-escalation cohorts of 3 patients. No dose limiting toxicities were identified and the maximum feasible dose (MFD) cohort of 20 mg/kg was extended with 12 additional patients. No higher than grade 3 CTCAE v3.0 toxicities, attributed to study drug, have been so far reported. Grade 3 toxicities, all reported in patients dosed with 20 mg/kg of CP-751,871, are increased GGT (4%) and fatigue (4%). Grade 2 toxicities include: anorexia (7%), diarrhea (7%), increased GGT (4%), hyperglycemia (4%), fatigue (4%), increased urinary frequency (4%), nausea (4%), increased ALT (4%) and increased AST (4%). Pharmacokinetic analysis is currently ongoing. No objective responses were observed. At the MFD, patients received a median of 4 cycles (1–16). Three patients were stable for > 6 months and one patient, currently at cycle 16, remains on study. An additional cohort of 12 adrenocortical cancer patients is under evaluation. Conclusions: These data indicate that CP-751,871 is safe and well tolerated. Due to its good safety profile, CP-751,871 may constitute a suitable targeted agent to use in combination with approved therapies in multiple tumor types. No significant financial relationships to disclose.

Phase I trial of sunitinib (S) and temsirolimus (T) in metastatic renal cell carcinoma (mRCC).

2014 ◽  
Vol 32 (4_suppl) ◽  
pp. 433-433
Author(s):  
Matthew T. Campbell ◽  
Randall E. Millikan ◽  
Emre Altinmakas ◽  
Lianchun Xiao ◽  
Nizar M. Tannir
Keyword(s):  
Phase I ◽  
Phase I Trial ◽  
Mtor Inhibitors ◽  
Median Number ◽  
Primary Objective ◽  
Best Response ◽  
Treatment Naïve ◽  
Grade 3 ◽  
Number Of Cycles ◽  
Mean Time

433 Background: Anti-VEGF agents and mTOR inhibitors are mainstay therapies in mRCC. Pre-clinical data suggests synergistic anti-tumor effect when combining these 2 classes. A previous phase I trial using sunitinib (S) 25 mg/d 4 wks on, 2 wks off, and temsirolimus (T) 15 mg/wk was stopped after 2 of the first 3 pts developed dose limiting toxicity (DLT). Methods: Pts with any subtype mRCC (PS 0-1) were eligible. Each cycle consisted of daily S for 14 days on, 7 days off, and weekly T. The continuous reassessment method (CRM) was used. The primary objective was to find the maximum tolerated doses (MTD) of S and T. The total planned accrual was 60 pts. Results: Accrual was stopped after 20 pts received study drugs. Median age was 63.5 years; 13 pts received prior targeted therapy, 7 pts were treatment naïve; median number of prior treatments 1 (range 0-6). Treatment cohorts (#pts, S, T, dose in mg): 2 (S12.5,T6), 1 (S25,T12.5), 1 (S12.5,T8), 8 (S12.5alt25,T9), 2 (S25,T6), 2 (S25alt37.5,T6), 2 (S37.5,T6), 2 (S37.5,T8). Dose reduction was required in 6 of 20 pts; the most common DLT was mucositis in 3 of 20 pts, followed by thrombocytopenia in 2 of 20 pts. The mean number of cycles for all pts was 6.6±5.36, with mean time on study 159±120 days. One pt experienced DLT in cycle 1 and received no study related imaging, 1 had a partial response, 16 pts had stable disease, and 2 pts had progressive disease (PD) as best response. A total of 21 grade 3/4 adverse events (AEs) attributed to drug occurred in 11 of 20 pts. Reasons for study discontinuation were PD in 12 pts, toxicity in 6 pts, and pt preference in 2 pts. There were no treatment related deaths. Conclusions: The MTD of S and T using the CRM were not reached due to premature trial closure. However, we believe S 37.5 mg/d, 2 wks on, 1 wk off, and T 8-10 mg weekly may well be close to MTD. Clinical trial information: NCT01122615.

Pooled analysis of phase I dose-escalation and dose cohort expansion studies of IMP4297, a novel PARP inhibitor, in Chinese and Australian patients with advanced solid tumors.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 3059-3059 ◽  
Author(s):  
Junning Cao ◽  
Pin Zhang ◽  
Paul L. de Souza ◽  
Bo Gao ◽  
Mark Voskoboynik ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Dose Level ◽  
Dose Escalation ◽  
Single Agent ◽  
Response To Treatment ◽  
Clinical Activity ◽  
Dose Cohort ◽  
Phase Ii Studies ◽  
Grade 3

3059 Background: Poly (ADP-ribose) polymerase (PARP) enzymes play critical roles in DNA damage detection and repair. IMP4297 is a novel, potent PARP1/2 inhibitor (IC50 6.27nM/1.57nM) and has demonstrated to be 20-fold more potent than Olaparib in anticancer animal models. Two phase I studies were performed to evaluate and characterize the tolerability and safety, pharmacokinetics, and antitumor activity of single agent IMP4297 in Chinese and Australian patients with advanced ovarian, breast, prostate and other solid tumors. Methods: Dose escalation used a 3+3 design with a modified Fibonacci escalation. Dose cohort expansion was planned after efficacy was observed at the lowest dose level. Patients received IMP4297 monotherapy orally once a day until disease progression or unacceptable toxicity. Results: As of Jan 12, 2019, 56 patients, including 23 BRCA mutation carriers (BRCA+), had been enrolled at 2-100 mg dose level. No DLT was observed. In these two studies, the most frequent treatment-related adverse events (TRAEs) were leukopenia (20%), followed by anemia (18%), nausea (18%) and thrombocytopenia (14%). The majority of TRAEs were grade 1 or 2. Grade 3 TRAEs occurred in five patients (anemia, n=2; vomiting, n=1; thrombocytopenia, n=1; elevated AST, n=1). Only one patient had a dose reduction due to grade 3 thrombocytopenia. No serious TRAEs were observed. In 15 BRCA+ patients who had measurable lesions, the ORR was 33% and the DCR was 80%. There were 4 BRCA+, platinum-sensitive ovarian cancer patients with an ORR of 75% and a DCR of 100%. One patient with somatic BRCA mutated urothelial carcinoma showed a 76% decrease in tumor size. Conclusions: IMP4297 has been well-tolerated with significant anti-tumor activity. The 100 mg daily dose was selected as the RP2D based on safety, pharmacokinetics and clinical activity, and will be further characterized in dose expansion and phase II studies. Tumor response to treatment (RECIST 1.1) in patients with measurable lesions. Clinical trial information: NCT03508011 and NCT03507543. [Table: see text]

scholarly journals Phase I/II Study of Escalating Doses of Thalidomide in Conjunction with Bortezomib and High Dose Melphalan As a Conditioning Regimen for Autologous Stem Cell Transplantation in Patients with Multiple Myeloma

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2154-2154
Author(s):  
Noa Biran ◽  
Shijia Zhang ◽  
Scott D. Rowley ◽  
David H. Vesole ◽  
Michele L. Donato ◽  
...  
Keyword(s):  
Phase I ◽  
Board Of Directors ◽  
Dose Escalation ◽  
Research Funding ◽  
Conditioning Regimen ◽  
High Dose ◽  
Advisory Committees ◽  
Common Grade ◽  
Grade 3 ◽  
High Dose Melphalan

Abstract Background: A regimen of escalating doses of thalidomide, in combination with bortezomib and high dose melphalan (Mel/Vel/Thal) was evaluated as a conditioning regimen for autologous stem cell transplantation (ASCT) in patients (pts) with multiple myeloma (MM) in a phase I/II study. Methods: Patients received Mel/Vel/Thal as a second of tandem ASCT if they achieved <CR to their first ASCT (tandem), or as conditioning for a salvage ASCT (salvage). Exclusion criteria were dose-intense therapy within 56 days, uncontrolled infections, severe organ dysfunction, Karnofsky score <70%, or painful grade 2 or greater peripheral neuropathy. Conditioning consisted of Vel 1.6 mg/m2 intravenously on days -4 and -1 with Mel 200 mg/m2 on day -2. Thal was given on days -5 through -1 and was administered in a planned step-wise dose escalation of 600, 800 and 1000 mg (in cohorts of 3 pts). Dexamethasone (Dex) 10-20 mg was given prior to Vel and Mel. All pts received G-CSF every other day starting day +3 until engraftment. Serious adverse events (SAEs) were graded according to CTCAE version 3. Results: Twenty-nine pts were enrolled: 9 in the phase 1 dose-escalation phase and an additional 20 pts in phase 2. In the phase I portion, all pts experienced somnolence, with grade 3 occurring in 1 pt at the 800 mg/day dose. Subsequently, Dex 40 mg was given with first dose of Thal at the 1000 mg level with decreased severity of somnolence. No dose limiting toxicities defined as ≥ grade 4 non-hematological SAEs occurred in the phase I portion, allowing full dose escalation with 9 pts enrolled. The maximum tolerated dose for Thal was not reached and the 1000 mg dose was chosen for the phase 2 dose expansion. No regimen related mortality occurred in either phase I or phase II portion of the study. All SAEs except lethargy and dizziness occurred after ASCT and were not attributed to Thal. The most common grade 1 and 2 non-hematologic toxicities included nausea (65.5%), mucositis (51.7%), diarrhea (48.3%), somnolence (48.3%), lethargy (27.6%), and vomiting (17.2%). The most common grade 3 non-hematologic adverse events (AEs) were neutropenic fever (58.6%), mucositis (6.9%), and somnolence (13.8%), which increased risk of falls. SAEs included somnolence (13.8%), tumor lysis syndrome (3.4%), and engraftment syndrome (3.4%). All transplant-related SAEs resolved by day +28 after ASCT. All pts achieved prompt hematological recovery with the median time to ANC >500/uL 10 days (range, 8-14 days), and platelet >20,000 12 days (range 9-26 days). All pts received at least one ASCT prior to enrolling on the study. Seventeen pts (59%) had interim salvage chemotherapy between their upfront and Mel/Vel/Thal ASCT (i.e. received a salvage ASCT), with median time from first to salvage ASCT 29 months. The remaining 12 (41%) went directly from an upfront ASCT Mel-based ASCT to the Mel/Vel/Thal ASCT (tandem ASCT) within 6 months of the first ASCT. Twenty-seven (93%) were Durie-Salmon stage III, and 13 (44%) had >2 prior lines of therapy. Of those who had Mel/Vel/Thal as a salvage ASCT, 70% had ≥3 prior lines of therapy. The overall response rate (ORR) was 69% with 38% complete remission. ORR for Mel/Vel/Thal compared to upfront Mel ASCT was 69% versus 62% with 11 patients achieving CR with Mel/Vel/Thal compared to 5 patients with Mel alone (Figure 1). Ten of 27 evaluable patients (37%) had an upgrade in response in the Mel/Vel/Thal salvage ASCT compared to their upfront ASCT: 2 pts (7%) went from PD to PR, 1 (4%) from SD to CR, 1 (4%) from PR to VGPR; 3 (11%) from PR to CR and 2 (7%) from VGPR to CR. Median PFS and OS were 9.3 and 65.4 months, respectively, with a median follow-up of 17.8 months. Of those who underwent tandem Mel followed by Mel/Vel/Thal ASCT the median PFS was 14.9 months with a median OS not yet reached at time of analysis. For the 17 patients who received a salvage Mel/Vel/Thal ASCT, median PFS from their upfront ASCT was 11.9 months, compared to 9.1 months with the salvage Mel/Vel/Thal ASCT. Conclusions: High-dose Thal up to 1000 mg daily for 5 days can be safely combined with Vel and dose-intense Mel as an ASCT conditioning regimen with acceptable toxicities. Confirmation of potential synergistic effects of this combination regimen will require an appropriately designed phase III study. Figure 1 Figure 1. Disclosures Biran: BMS: Research Funding; Merck: Research Funding; Takeda: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau. Skarbnik:Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead Sciences: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Genentech: Honoraria, Speakers Bureau; Jazz Pharmaceuticals: Honoraria, Speakers Bureau. Siegel:Novartis: Honoraria, Speakers Bureau; Merck: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau; Karyopharm: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau.

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