Dasatinib In Children and Adolescents with Relapsed or Refractory Leukemia: Results of the CA180018 Phase 1 Dose-Escalation Study of the Innovative Therapies for Children with Cancer (ITCC) Consortium

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2265-2265 ◽  
Author(s):  
C. Michel Zwaan ◽  
Carmelo Rizzari ◽  
Francoise Mechinaud ◽  
Donna L Lancaster ◽  
Pamela R. Kearns ◽  
...  
Keyword(s):  
Dose Escalation ◽  
Maximum Concentration ◽  
Phase 1 ◽  
Molecular Response ◽  
Cell Transplant ◽  
Phase 2 ◽  
Newly Diagnosed ◽  
Dose Escalation Study ◽  
Safety And Efficacy ◽  
Grade 3

Abstract Abstract 2265 Background: Pediatric relapsed/refractory leukemia portends a poor prognosis and more effective therapies are urgently needed. Dasatinib is a potent oral BCR-ABL inhibitor approved for treating adults with chronic myeloid leukemia (CML) or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) resistant or intolerant to imatinib. Dasatinib also has activity against SRC-family kinases and KIT. A phase 3 trial of dasatinib vs imatinib in adults with newly diagnosed with CML in chronic phase (CP) showed superior efficacy of dasatinib with good tolerability (Kantarjian et al. NEJM 2010:362:2260). Methods: The CA180018 trial is a component of a European Medicines Agency-approved comprehensive Pediatric Investigation Plan for dasatinib aimed at improving outcomes in pediatric leukemias. This trial is being conducted via the ITCC consortium in 7 countries (15 centers) as a stratified phase 1 dose-escalation study. The primary aim is to establish a safe and effective phase 2 dose of dasatinib in children/adolescents with subtypes of relapsed/refractory leukemia. Secondary objectives include safety, pharmacokinetics (PK), and rates of hematologic, cytogenetic, and molecular response (cytogenetic/molecular responses in Ph+ only). Patients (pts) were stratified into 3 disease strata: Stratum 1, imatinib-resistant/intolerant Ph+ CML-CP; Stratum 2/3, advanced CML resistant to imatinib or Ph+ ALL relapsed/refractory after imatinib or Ph+ AML in ≥2nd relapse (original strata merged by protocol amendment due to slow enrolment); and Stratum 4, ≥2nd relapse of Ph– ALL or AML. Starting doses were 60, 80, 100, and 120 mg/m2 once daily, with dose escalations based on safety and efficacy. Intrapatient dose escalation was allowed for lack of response. Results: The study opened in March 2006 and closed to accrual in October 2009. 58 pts have been treated, of which 50 (86%) completed therapy by data cut-off of May 2010. No pts with Ph+ AML were enrolled. All pts had prior therapy, including imatinib in 59% (all Ph+ pts), anagrelide or hydroxyurea in 22%, interferon in 3%, other chemotherapy in 69%, radiotherapy in 43%, and stem cell transplant in 50%. Median age (yrs) was 11, including 2 pts (3%) aged <2, 32 (55%) aged 2–11, 23 (40%) aged 12–18, and 1 (2%) aged >18. 39 pts (67%) were male. No pt with Ph– AML had a KIT mutation. Median durations of therapy (range) were: Stratum 1, 11.3 mos (2.3–47.9); Stratum 2/3, 3.0 mos (0.5–24.6); and Stratum 4, 1.1 mos (<0.1–3.4). Dasatinib up to 120 mg/m2, including long-term therapy, was well tolerated. Common drug-related toxicities (≥10%) were: nausea (grade 1/2 in 16 pts [28%], grade 3 in 1 [2%]); headache (grade 1/2 in 11 [19%], grade 3 in 2 [3%]); diarrhea (grade 1/2 in 12 [21%]); vomiting (grade 1/2 in 9 [16%], grade 3 in 1 [2%]); rash (grade 1/2 in 9 [16%]); and pain in extremity (grade 1/2 in 6 [10%]). Pleural effusion occurred in 2 pts (3%) at grade 1 and 1 pt (2%) at grade 3. Two dose-limiting toxicities were seen in Stratum 4: grade 4 anaphylaxis 5 h after first dose (60 mg/m2) and grade 3 upper GI bleed on Day 6 (120 mg/m2) in a pt with platelet count of 16×109/L. Maximum tolerated dose has not been established. PK parameters, analyzed in 52 pts to date, showed high interpatient and intrapatient variability. Dasatinib was rapidly absorbed with median time to maximum concentration of 1.0 h irrespective of dose. Mean half-life ranged from 2.1–3.6 h. With dasatinib 60, 80, 100, or 120 mg/m2, area under the curve was 374, 530, 424, and 606 ng.h/mL and maximum concentration was 113, 138, 114, and 183 ng/mL, respectively. Treatment responses were seen in Ph+ pts who received dasatinib 60 or 80 mg/m2. In Stratum 1 (CML-CP; n=17), rates were complete hematologic response (HR) in 16 (94%), complete cytogenetic response (CCyR) in 14 (82%), major molecular response (MMR) in 6 (35%), and complete molecular response in 4 (24%). In Stratum 2/3 (advanced CML/Ph+ ALL; n=17), rates were major HR in 10 (59%), CCyR in 12 (71%), and MMR in 0/2 pts with advanced CML assessed to date. No pt in Stratum 4 responded (Ph– ALL/AML; n=24). Final data will be presented. Conclusions: This trial shows the safety and efficacy of dasatinib in pediatric pts with Ph+ leukemias and supports the feasibility of evaluating new agents in children with rare malignancies through cooperative group efforts. A phase 2 study is underway to further evaluate dasatinib in children/adolescents with Ph+ leukemias, including newly diagnosed CML. Disclosures: Zwaan: Bristol-Myers Squibb: Consultancy. Off Label Use: Dasatinib treatment of pediatric leukemias. Rosenberg: Bristol-Myers Squibb: Employment, Equity Ownership. Herdlicka: Bristol-Myers Squibb: Employment. Derreumaux: Bristol-Myers Squibb: Employment. Agrawal: Bristol-Myers Squibb: Employment.

Preliminary safety and efficacy of IPI-145, a potent inhibitor of phosphoinositide-3-kinase-δ,γ, in patients with relapsed/refractory lymphoma.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 8518-8518 ◽  
Author(s):  
Steven M. Horwitz ◽  
Ian Flinn ◽  
Manish R. Patel ◽  
Anas Younes ◽  
Francine M. Foss ◽  
...  
Keyword(s):  
T Cell ◽  
Dose Escalation ◽  
Phase 1 ◽  
Single Agent ◽  
Clinical Activity ◽  
Dose Escalation Study ◽  
Safety And Efficacy ◽  
Early Results ◽  
Refractory Lymphoma ◽  
Grade 3

8518 Background: Phosphoinositide-3-kinases (PI3Ks) are pivotal in cell signaling and regulate a variety of cellular functions relevant to oncogenesis. IPI-145, a potent oral inhibitor of the PI3KEδ and PI3K-γ isoforms, is in clinical development for patients (pts) with hematologic malignancies. Early results in pts with relapsed/refractory lymphoma from an ongoing Phase 1 study are reported here. Methods: This dose-escalation study evaluates the safety, maximum tolerated dose (MTD), clinical activity, and pharmacokinetics (PK) of IPI-145. Expansion cohorts (EC) < MTD are allowed. IPI-145 is given orally twice daily (BID) in 28-day cycles. Tumor response is based on standard disease-specific criteria. Results: 55 pts have been dosed with IPI-145. PK, available through 50 mg BID, are linear with complete inhibition of PI3K-δ at doses > 15 mg BID and increasing suppression of PI3K-γ with increasing dose. In the 36 pts with lymphoma who received 15 mg to 75 mg BID, the median [range] number of cycles was 2.4 [0.1–10] and 67% remain on study. Treatment-related adverse events (TRAEs) occurred in 50% of pts with lymphoma. Neutropenia and increased ALT were the most common ≥ Grade 3 TRAEs (4 pts each) and were not associated with increasing dose. > Grade 3 ALT elevations were more common in lymphoma pts (18%) compared to non-lymphoma pts (5%). Among evaluable pts with lymphoma (n=27), early clinical activity was observed in T-cell (n=6, 1 CR, 1 PR, 1 SD) and aggressive/indolent B-cell (n=21, 2 CR, 9 PR, 5 SD) lymphoma pts at ≤ 75 mg BID. 92% of responses were observed by 3 months. Conclusions: IPI-145 appeared well tolerated and has shown clinical activity in pts with relapsed/refractory advanced B- and T-cell lymphoma across the range of doses examined. The single agent MTD has not been determined and dose escalation continues. Updated safety and efficacy data from pts with lymphoma enrolled in dose escalation or ECs evaluating 25 mg BID and a higher dose (< MTD) of IPI-145 will be presented. Clinical trial information: NCT01476657.

scholarly journals Phase 1 dose-escalation study of a novel oral PI3K/mTOR dual inhibitor, LY3023414, in patients with cancer

2020 ◽  
Vol 38 (6) ◽  
pp. 1836-1845
Author(s):  
Shunsuke Kondo ◽  
Masaomi Tajimi ◽  
Tomohiko Funai ◽  
Koichi Inoue ◽  
Hiroya Asou ◽  
...  
Keyword(s):  
Dose Escalation ◽  
Phase 1 ◽  
Mammalian Target Of Rapamycin ◽  
Japanese Patients ◽  
Competitive Inhibitor ◽  
Primary Objective ◽  
Dose Escalation Study ◽  
Dual Inhibitor ◽  
Advanced Malignancies ◽  
Grade 3

Summary LY3023414 is an oral, selective adenosine triphosphate-competitive inhibitor of class I phosphatidylinositol 3-kinase isoforms, mammalian target of rapamycin, and DNA-protein kinase in clinical development. We report results of a 3 + 3 dose-escalation Phase 1 study for twice-daily (BID) dosing of LY3023414 monotherapy in Japanese patients with advanced malignancies. The primary objective was to evaluate tolerability and safety of LY3023414. Secondary objectives were to evaluate pharmacokinetics and to explore antitumor activity. A total of 12 patients were enrolled and received 150 mg (n = 3) or 200 mg (n = 9) LY3023414 BID. Dose-limiting toxicities were only reported at 200 mg LY3023414 for 2 patients with Grade 3 stomatitis. Common treatment-related adverse events (AEs) across both the dose levels included stomatitis (75.0%), nausea (66.7%), decreased appetite (58.3%), diarrhea, and decreased platelet count (41.7%), and they were mostly mild or moderate in severity. Related AEs Grade ≥ 3 reported for ≥1 patient included anemia, stomatitis, hypophosphatemia, and hyperglycemia (n = 2, 16.7%). Two patients discontinued due to AEs (interstitial lung disease and stomatitis). No fatal events were reported. The pharmacokinetic profile of LY3023414 was characterized by rapid absorption and elimination. Five patients had a best overall response of stable disease (150 mg, n = 3; 200 mg, n = 2) for a 55.6% disease control rate. LY3023414 up to 200 mg BID is tolerable and safe in Japanese patients with advanced malignancies.

scholarly journals A phase 1 dose-escalation study of intraperitoneal cisplatin, intravenous/intraperitoneal paclitaxel, bevacizumab, and olaparib for newly diagnosed ovarian cancer

2020 ◽  
Vol 157 (1) ◽  
pp. 214-221
Author(s):  
Karen A. Cadoo ◽  
Rachel N. Grisham ◽  
Roisin E. O'Cearbhaill ◽  
Nicole N. Boucicaut ◽  
Melissa Henson ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Dose Escalation ◽  
Phase 1 ◽  
Newly Diagnosed ◽  
Dose Escalation Study

Navitoclax (ABT-263) Plus Fludarabine/Cyclophosphamide/Rituximab (FCR) or Bendamustine/Rituximab (BR): A Phase 1 Study In Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia (CLL)

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2455-2455 ◽  
Author(s):  
Thomas J. Kipps ◽  
William G. Wierda ◽  
Jeffrey A. Jones ◽  
Lode J. Swinnen ◽  
Jianning Yang ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Chronic Lymphocytic Leukemia ◽  
Dose Escalation ◽  
Research Funding ◽  
Phase 1 ◽  
B Cell Lymphoma ◽  
Lymphocytic Leukemia ◽  
Cell Transplant ◽  
Phase 2 ◽  
Anti Tumor Activity

Abstract Abstract 2455 Background: Navitoclax (ABT-263), a novel, orally bioavailable, small molecule, binds with high affinity (Ki ≤1nM) to Bcl-2, Bcl-xL, and Bcl-w, promoting apoptosis. In vitro, navitoclax shows potent targeted cytotoxicity (EC50 ≤ 1μM) against T and B lymphoid malignancies that over-express Bcl-2. A phase 1 trial demonstrated oral navitoclax monotherapy to be well-tolerated and to have anti-tumor activity in patients (pts) with chronic lymphocytic leukemia (CLL). However, thrombocytopenia (TCP) was the dose-limiting toxicity (DLT). Phase 3 studies showed improved outcomes in CLL pts with the fludarabine/cyclophosphamide/rituximab (FCR) combination, and a phase 2 trial showed bendamustine/rituximab (BR) to be effective for pts with relapsed or refractory CLL. Navitoclax enhanced R (monotherapy and in combination with chemotherapy) efficacy in preclinical models of B-cell lymphoma. Methods: This is an ongoing, international, phase 1 dose-escalation study to evaluate the safety and pharmacokinetics (PK) of oral navitoclax in combination with FCR (Arm A) or BR (Arm B) in pts with relapsed/refractory CLL. Secondary objectives are efficacy endpoints (PFS, ORR, TTP, OS, duration of response). Eligible pts had measurable disease, ECOG performance score ≤1, ANC ≥100/μL, platelets ≥100,000/mm3, and hemoglobin ≥9.0 g/dL. Preliminary results are reported. After obtaining informed consent, pts were assigned to Arm A or Arm B based on physician preference, each consisting of 28-day dose-escalation cycles with once-daily, pre-infusion, navitoclax treatment on Days 3–5 of Cycle 1 and Days 1–3 of subsequent cycles. In both arms, R was 375 mg/m2 on Day 1 of Cycle 1; and 500 mg/m2 on Day 2 of Cycle 2 and on Day 1 of subsequent cycles. In Arm A, F 25 mg/m2 and C 175 mg/m2 were dosed on Days 2–4 in Cycles 1 and 2, and on Days 1–3 in subsequent cycles. In Arm B, B was dosed at 70 mg/m2 on Days 2 and 3 of Cycles 1 and 2, and on Days 1 and 2 in subsequent cycles. Navitoclax starting dose was 110 mg daily. Dose escalation to the next cohort (200 mg) was according to a continuous reassessment model. Tumor responses were evaluated using NCI-WG 1996 criteria. Pts could continue on navitoclax therapy for 1 yr in the absence of progressive disease or significant toxicity. Results: As of July 2010, 7 pts enrolled in the initially prioritized Arm B (BR+navitoclax); all completed the first cohort of 110 mg (median age 60 yr [range 55–72]). Study sites are currently enrolling pts in Arm A (FCR+navitoclax); 2 pts have enrolled to date. The median number of prior therapies was 2 (range 1–7). One pt had a DLT of elevated AST (Arm B, 110 mg cohort) and 1 pt had a DLT of neutropenic fever (Arm A, 110 mg cohort). In Arm B, neither TCP nor neutropenia have been DLTs. For the 7 pts with navitoclax-related AEs, the most common were diarrhea (3 pts), nausea (5 pts), and fatigue (3 pts). Seven pts remain on study; 2 pts discontinued due to disease progression and 2 withdrew per physician preference. In Arm B, preliminary antitumor best responses were assessable in 4 pts who received 2 cycles; 1 CRi in a pt with del17p- (based on lymph node [LN] response and no morphologic evidence of CLL in the bone marrow), 2 unconfirmed CRs (based on LN response and no bone marrow at this time), and 1 PR in a pt with del17p- (this pt subsequently received an allogeneic stem cell transplant). Preliminary PK results for the Arm B 110 mg cohort indicated that navitoclax PK was similar in Cycle 1 (navitoclax+BR) and Cycle 2 (navitoclax alone), and appeared comparable to PK in the navitoclax monotherapy study. Conclusions: Early results show that the combination of navitoclax with BR is well-tolerated, without DLTs of TCP or neutropenia, and show evidence of anti-tumor activity. Data are limited in the FCR portion of the study. The maximum tolerated dose of navitoclax has not been reached. Accrual is ongoing and following completion of the dose-escalation components of this study, expanded cohorts of pts will be assessed using the recommended phase 2 dose of navitoclax to further assess the tolerability and dose, and to continue to explore for efficacy signals in combinations. Preliminary data in combination with BR are encouraging. Disclosures: Kipps: Abbott Laboratories: Research Funding; Genentech/Roche: Research Funding. Wierda: Abbott: Research Funding; Genentech: Honoraria, Speakers Bureau. Jones: Glaxo Smith-Kline: Consultancy; Abbott: Research Funding. Swinnen: Genentech: Membership on an entity's Board of Directors or advisory committees, Research Funding. Yang: Abbott: Employment. Cui: Abbott: Employment. Busman: Abbott: Employment. Krivoshik: Abbott: Employment. Enschede: Abbott: Employment. Humerickhouse: Abbott: Employment.

Phase 1 study of CPX-1, a fixed ratio formulation of irinotecan (IRI) and floxuridine (FLOX), in patients with advanced solid tumors

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 2014-2014 ◽  
Author(s):  
G. Batist ◽  
K. Chi ◽  
W. Miller ◽  
S. Chia ◽  
F. Hasanbasic ◽  
...  
Keyword(s):  
Dose Escalation ◽  
Phase 1 ◽  
Fixed Ratio ◽  
Compression Fracture ◽  
Drug Combinations ◽  
Molar Ratio ◽  
Open Label ◽  
Dose Escalation Study ◽  
Grade 3

2014 Background: In vitro studies have shown that varying the ratio of individual agents in drug combinations can result in synergistic, additive or antagonistic activity against tumor cells. CPX-1 is a liposomal formulation of IRI and FLOX in a fixed 1:1 molar ratio which was selected as optimal in vitro and confirmed to be synergistic in vivo in preclinical tumor models. CPX-1 overcomes the dissimilar pharmacokinetics (PK) of the individual drugs, enables sustained maintenance of this ratio after IV administration, and was evaluated in a Phase I open-label, dose-escalation study. Methods: Starting dose was 30 U/m2 (1 Unit of CPX-1 contains 1 mg IRI + 0.36 mg FLOX) given on day 1 and 15 of each 28-day cycle. Dose escalation was by modified Fibonacci with 4 subjects/cohort. Eligibility included: ≥ 18 yo; advanced solid tumor; ECOG PS ≤ 2; adequate bone marrow/liver/renal function. PK analysis was done on day 1 and 15 of the first cycle. Results: 26 subjects (16M:10F), median age 54.5 y (21–72), all with prior therapy, enrolled in 6 cohorts with the 5th cohort expanded to 6 subjects. Diagnoses: 8 colorectal, 3 pancreatic, 3 ovarian, 2 breast, 2 gastric, 2 esophageal, 2 sarcomas, 1 renal cell, 1 prostate, 1 NSCLC and 1 sphenoid sinus. Response: 20 subjects evaluable: 2 confirmed PRs (NSCLC 8+ wks; Colon 13+ wks, in a patient with prior IRI exposure) and 13 with SD (8–24+wks). Safety: DLTs were observed at the 6th dose level: 4 subjects with DLTs: 3 diarrhea (one resulting in death due to dehydration/ARF) and one neutropenia. Other possibly related grade 3 and 4 events included one each of: grade 3 diarrhea, grade 3 vomiting, grade 3 neutropenia, grade 3 fatigue, grade 3 compression fracture and arthralgia and pulmonary embolism grade 4. PK: In all 14 subjects analyzed to date the 1:1 molar ratio of IRI to FLOX was maintained for 24 hours and metabolites 5-FU and SN-38 were present in the plasma. Conclusions: CPX-1 represents a new approach to developing drug combinations in which drug ratios are pre-selected in vitro based on optimal antitumor activity and maintained systemically through pharmacokinetic control. Phase 2 studies are planned with a recommended dose of 210U/m2 of CPX-1. [Table: see text]

MLN9708, an investigational proteasome inhibitor, in patients (pts) with relapsed/refractory lymphoma: Emerging data from a phase I dose-escalation study.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 8064-8064 ◽  
Author(s):  
Peter Martin ◽  
Julie E. Chang ◽  
Robert M. Rifkin ◽  
Ai-Min Hui ◽  
Deborah Berg ◽  
...  
Keyword(s):  
Dose Escalation ◽  
Proteasome Inhibitor ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
20S Proteasome ◽  
Multiple Time ◽  
Cell Transplant ◽  
Dose Escalation Study ◽  
Refractory Lymphoma ◽  
Grade 3

8064 Background: MLN9708 is a reversible, orally bioavailable, specific 20S proteasome inhibitor. This study (NCT00893464) studied the safety and determined the MTD of IV MLN9708 in pts with relapsed/refractory lymphoma, and characterized pharmacokinetics (PK) and pharmacodynamics (PD). Methods: Pts aged ≥18 yrs who had failed ≥2 chemotherapeutic regimens received IV MLN9708 on days 1, 8, and 15 of 28-day cycles until disease progression or unacceptable toxicity. One pt was enrolled at the 0.125 mg/m2 starting dose; dose doubling proceeded with 1 pt at each dose up to 1.0 mg/m2. Dose escalation occurred in ≤40% increments using a standard 3+3 scheme based on DLT occurrence in cycle 1. Blood samples were collected at multiple time points after dosing on days 1 and 15 of cycle 1 for PK/PD analyses. Results: At data cut-off (Dec 1 2011), 21 pts had been enrolled and treated: 1 each at 0.125, 0.25, 0.5 and 1 mg/m2, 4 at 1.4 mg/m2, 7 at 1.76 mg/m2, and 6 at 2.34 mg/m2. Median age was 57 yrs (range 23–78); 57% were male. Median number of prior therapies was 5; 29% had prior radiation, 24% prior stem cell transplant. Histologies included T-cell lymphoma (n=5), Hodgkin lymphoma (n=3), follicular lymphoma (n=2), DLBCL (n=1) and other indolent B-cell lymphoma (n=7). Pts had received a median of 2 cycles (range 1–22); 2 DLTs were seen (neutropenia at 1.76 and 2.34 mg/m2). All pts experienced drug-related AEs, including fatigue (48%), nausea (29%), diarrhea (29%), pyrexia, thrombocytopenia, and vomiting (each 24%). 43% had drug-related grade ≥3 AEs, 1 pt discontinued due to drug-related grade 3 neutropenia (2.34 mg/m2). Three pts had drug-related peripheral neuropathy (1 grade 1, 2 grade 2). There were no on-study deaths. Of 18 response-evaluable pts, 3 achieved PR (including 2 who remain in response and on-study for >1 yr) and 4 SD. PK analyses showed linear PK (0.5–2.34 mg/m2) and a terminal half-life of ~6–9 days. There was a dose-dependent increase in maximal whole blood 20S proteasome inhibition. Conclusions: These data suggest IV MLN9708 is generally well tolerated, with infrequent PN, and is clinically active in pretreated lymphoma pts. The trial is ongoing and updated data will be presented.

A phase II study of dasatinib therapy in children and adolescents with newly diagnosed chronic phase chronic myelogenous leukemia (CML-CP) or Philadelphia chromosome-positive (Ph+) leukemias resistant or intolerant to imatinib.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. TPS9594-TPS9594
Author(s):  
Michel Zwaan ◽  
Linda C. Stork ◽  
Yves Bertrand ◽  
Lia Gore ◽  
Nobuko Hijiya ◽  
...  
Keyword(s):  
Phase I ◽  
Phase Ii ◽  
Dose Escalation ◽  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
Chronic Phase ◽  
Myelogenous Leukemia ◽  
Molecular Response ◽  
Newly Diagnosed ◽  
Dose Escalation Study

TPS9594 Background: Dasatinib is a BCR-ABL inhibitor approved for treatment in adult patients (pts) with newly diagnosed Ph+ CML-CP; CML resistant/intolerant to prior therapy, including imatinib; and Ph+ acute lymphoblastic leukemia (ALL). There are no established dasatinib treatment regimens for children/adolescents with relapsed/refractory leukemia, but pediatric trials are underway. A phase I dose-escalation study of dasatinib in pediatric pts with refractory solid tumors (n=28) and imatinib-refractory, Ph+ leukemia (n=11) reported a maximum tolerated dose of 85 mg/m2 twice daily in solid-tumor pts and at least a partial cytogenetic response (CyR) in all evaluable CML pts (n=9) (Aplenc, J Clin Oncol 2011). Preliminary results from a phase I dose-escalation study in pediatric pts with subtypes of relapsed/refractory leukemia (NCT00306202) indicate that dasatinib was well tolerated up to 120 mg/m2 (Zwaan, Blood 2010 [abstr 2265]). Further study of dasatinib in pediatric pts is warranted. Methods: To evaluate the safety and efficacy of dasatinib monotherapy in children/adolescents with newly diagnosed CML-CP or Ph+ leukemias resistant/intolerant to imatinib, a phase II nonrandomized, global study of dasatinib in pts birth to <18 y is ongoing (NCT00777036): Cohort 1 (C1), Ph+ CML-CP pts resistant/intolerant to imatinib; Cohort 2 (C2), Ph+ ALL, accelerated or blast phase CML pts resistant/intolerant to or relapsed after imatinib therapy; or Cohort 3 (C3), newly diagnosed, treatment-naïve Ph+ CML-CP pts. Treatments are once daily with dasatinib 60 mg/m2 (C1/C3) or 80 mg/m2 (C2) for ≥24 months. Primary endpoints are major CyR (C1), complete hematologic response (C2), and complete CyR (C3). Secondary endpoints include safety, tolerability, best response, time to/duration of response, survival, and molecular response rates. BCR-ABL mutations are evaluated. First patient first visit was March 2009; estimated trial completion is September 2016. As of January 2012, 63 pts (n=27 aged <12 y; n=36 aged ≥12 y) have been treated in C1/C2 (n=41) and C3 (n=22). Enrollment is ongoing at 79 sites.

Phase 1 dose escalation study of MEDI-565, a bispecific T-cell engager that targets human carcinoembryonic antigen (CEA), in patients with advanced gastrointestinal (GI) adenocarcinomas.

2016 ◽  
Vol 34 (4_suppl) ◽  
pp. 320-320
Author(s):  
Michael J. Pishvaian ◽  
Michael Morse ◽  
Jennifer T. McDevitt ◽  
Song Ren ◽  
Gabriel Robbie ◽  
...  
Keyword(s):  
T Cell ◽  
Antitumor Activity ◽  
Dose Escalation ◽  
Half Life ◽  
High Titer ◽  
Phase 1 ◽  
Single Chain ◽  
Dose Escalation Study ◽  
Human T Cell ◽  
Grade 3

320 Background: MEDI-565, a bispecific single-chain antibody, targets human CEA on tumor cells and the CD3 epsilon subunit of the human T-cell receptor complex. In murine models, MEDI-565 showed antitumor activity in CEA-expressing tumors (J Immunother 2009;34:341-52). Methods: This phase 1, multicenter, open-label, dose-escalation study enrolled adults with GI adenocarcinomas (including esophageal, gastric, small intestine, colorectal, biliary tract, and pancreatic). MEDI-565 was given intravenously over 3 h on days 1–5 in 28-day cycles, with 4 single-patient (pt) (0.75–20 μg) and 5 standard 3+3 escalation (60 μg–3 mg; 1.5–7.5 mg with dexamethasone [dex]) cohorts. Primary objective was to determine the maximum tolerated dose (MTD); secondary objectives were to evaluate pharmacokinetics (PK), antidrug antibody (ADA), and antitumor activity. Results: Study enrolled39 pts: mean age 59 y; 56% male; 28 (72%) colorectal, 6 (15%) pancreatic, 5 (13%) other. Dose-limiting toxicities (grade ≥ 3 nonhematologic) were seen in 4 pts (2 at 3-mg; 2 at 7.5-mg + dex): hypoxia (n = 2), diarrhea, and cytokine release syndrome (CRS). Grade 3 treatment-related adverse events (AEs) seen in 5 pts: diarrhea, CRS, increased alanine aminotransferase, hypertension (all n = 1), and hypoxia (n = 2). Treatment-related serious AEs seen in 6 pts: diarrhea, vomiting, pyrexia, CRS (all n = 1), and hypoxia (n = 2). Five pts discontinued treatment due to AEs: diarrhea, CRS, central nervous system metastases, and hypoxia (n = 2). MEDI-565 exposures increased in approximately dose-proportional manner, with clearance (35–77 L/d) and half-life (2–7 h) typical of drug class. ADA had minor impact; 19 pts (48.7%) had ADAs, 5/39 (12.8%) with high titer, with decreased MEDI-565 concentrations in 2 pts. Plasma inflammatory cytokines were elevated posttreatment in several pts at 1.5- and 3-mg (no dex) dose levels. No objective responses were observed; 11 (28%) pts had stable disease as best response. Conclusions: The MTD of MEDI-565 in pts with GI adenocarcinomas was 5 mg with dex. PK was linear, with fast clearance and short half-life. No objective responses were observed. Clinical trial information: NCT01284231.

Phase 1 single-center, dose escalation study of D2C7-IT administered intratumorally via convection-enhanced delivery for adult patients with recurrent malignant glioma.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e13532-e13532 ◽  
Author(s):  
Dina Randazzo ◽  
Annick Desjardins ◽  
Vidyalakshmi Chandramohan ◽  
John H. Sampson ◽  
Katherine B. Peters ◽  
...  
Keyword(s):  
Dose Level ◽  
Dose Escalation ◽  
Phase 1 ◽  
Genetically Engineered ◽  
Convection Enhanced Delivery ◽  
Dose Escalation Study ◽  
Who Grade ◽  
Recombinant Immunotoxin ◽  
Level 3 ◽  
Grade 3

e13532 Background: D2C7 immunotoxin (D2C7-IT) is a dual-specific recombinant immunotoxin consisting of EGFR-wt and EGFRvIII monoclonal antibodies with a genetically engineered Pseudomonas exotoxin, PE-38KDEL. The primary objective is to determine the maximum tolerated dose of D2C7-IT when delivered intratumorally by convection enhanced delivery (CED). Methods: Inclusion criteria includes subjects with a single, recurrent supratentorial WHO grade III or IV glioma, KPS ≥ 70 and a washout of chemotherapy, bevacizumab or study drug of ≥ 4 weeks. Prior to administration of D2C7-IT, recurrent tumor must be confirmed by histopathology. A minimum of 2 subjects are accrued by dose level. Results: Currently, 23 subjects have been treated (16 male, 7 female) with a median age of 54 years. Out of 9 dose levels, 2 subjects have been treated at every dose except for 4 at dose level 3 (120 ng/ml) and 5 at dose 6 (405ng/ml). Adverse events possibly, probably or definitely related to D2C7-IT are mostly grade 1 or 2 events consisting of, but not limited to: intracranial hemorrhage (n = 1), stroke (n = 2), headache (n = 15), seizure (n = 5), confusion (n = 4), paresthesia (n = 4), dysarthria (n = 1), dysphasia (n = 4), visual disturbances (n = 7), fatigue (n = 4), gait disturbance (n = 2), elevated transaminases (n = 5), decreased platelets (n = 3), decreased neutrophil count (n = 1), nausea (n = 3), vomiting (n = 1), and thromboembolic event (n = 1). There was 1 dose limiting toxicity (grade 4 seizure at dose level 3), 2 grade 3 headaches and 1 grade 3 elevated ALT. 14 subjects are still alive with 6 remaining on study. So far, the longest survival time from infusion is 18.2+ months. Conclusions: D2C7-IT infusion via CED is safe with encouraging results. This dose escalation Phase I study is ongoing and will set the stage for the Phase II trial. Clinical trial information: NCT02303678.

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