Lenalidomide in Combination with Melphalan and Dexamethasone in Patients with Newly-Diagnosed Light-Chain (AL)-Amyloidosis: a Multicenter Phase I/II Dose Escalation Study.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 427-427
Author(s):  
Philippe Moreau ◽  
Arnaud Jaccard ◽  
Lotfi Benboubker ◽  
Bruno Royer ◽  
Xavier Leleu ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Level ◽  
Dose Escalation ◽  
Treatment Delay ◽  
Phase Iii ◽  
Al Amyloidosis ◽  
Hematologic Toxicity ◽  
Newly Diagnosed ◽  
Dose Escalation Study

Abstract Abstract 427 Introduction: The combination of melphalan and dexamethasone (M-dex) is widely used in patients with newly diagnosed AL-amyloidosis, with hematologic and organ response rates of 50 and 40%, respectively (Jaccard, New Engl J Med 2007). Lenalidomide has also been evaluated, mainly in the relapse setting, and the initial dose of 25 mg/day was poorly tolerated. However, a 15 mg/day dose regimen was well tolerated and effective, with both hematologic and organ responses (Dispenzieri, Blood 2007 & Sanchorawala, Blood 2007). Combining M-dex with lenalidomide could increase the response rate but the toxicity of this regimen is still unknown. Thus we have initiated a multicenter single-arm open-label phase I/II dose escalation study of lenalidomide administered in combination with M-dex. Patients and methods: The primary endpoint was the incidence of dose limiting toxicities (DLT) during the first cycle of lenalidomide at a given dose level in order to determine the maximum tolerated dose (MTD). In addition to melphalan 0.18mg/kg/day from day 1-4 of each 28 day cycle and dexamethasone 40mg/day from day 1- 4 of each 28 day cycle, patients were successively exposed to escalating doses of lenalidomide (5, 10, 15 and 20 mg once daily on days 1–21 of a 28 day cycle). Nine cycles were planned at each dose level, according to safety and efficacy. DLT was defined using National Cancer Institute common toxicity criteria during the first 4 weeks of treatment (one cycle) as the following: at least grade 2 cardiac arrhythmia, at least grade 3 non hematologic toxicity, grade 4 neutropenia lasting >7 days or any other Grade 4 hematologic toxicity, or treatment delay due to toxicity that occurred during the first cycle. Organ involvement and the response to therapy were evaluated according to the international consensus guidelines (Gertz Am J Hem 2005). Results: From 03/2008 to 01/2009, 27 patients were enrolled. 1 patient withdrew consent after the first month of therapy and was thereafter lost to follow-up. No DLT was observed among the patients treated at 5 (3 patients), 10 (4 patients) and 15 mg lenalidomide/day (13 patients). 2 / 6 patients treated in cohort 4 at the dose of 20 mg lenalidomide/day experienced DLT, grade 4 hematologic toxicity and treatment delay due to toxicity; thus 15 mg lenalidomide/day, in combination with M-dex, was considered as the MTD. With a median follow-up of 12 months (7-17), 20/26 patients (77%) are alive. Six deaths were observed, due to progressive disease in 5 cases (median time from diagnosis 1 month, 1 to 3), or cholangiocarcinoma in 1 case (7 months after the diagnosis of AL-amyloidosis). Hematologic and organ responses were observed in 68 and 50% of the cases, respectively. At the reference date of Aug15th, 2009 none of the responding patients experienced progression, and all were able to receive 9 cycles according to the protocol.Conclusion: The recommended dose of lenalidomide in combination with M-dex in subjects with AL-amyloidosis previously untreated is 15 mg/day (days 1-21 of a 28 day cycle). Response and survival rates compare favourably with those achieved with M-dex alone. A prospective phase III trial comparing M-dex with M-dex lenalidomide should be valuable. Disclosures: Moreau: celgene: Speakers Bureau. Off Label Use: lenalidomide in combination with melphalan and dexamethasone in patients with AL-amyloidosis. Jaccard:celgene: Speakers Bureau. Salles:Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Alakl:Celgene: Employment. Harousseau:celgene: Speakers Bureau. Fermand:celgene: Speakers Bureau.

A Multicenter Phase I/II Dose Escalation Study of Lenalidomide in Combination with Melphalan and Dexamethasone in Subjects with Newly-Diagnosed Light-Chain (AL)-Amyloidosis.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1732-1732
Author(s):  
Philippe Moreau ◽  
Arnaud Jaccard ◽  
Lotfi Benboubker ◽  
Bruno Royer ◽  
Valerie Coiteux ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Escalation ◽  
Response Rate ◽  
Standard Dose ◽  
High Dose ◽  
Al Amyloidosis ◽  
Hematologic Toxicity ◽  
Newly Diagnosed ◽  
Open Label ◽  
Dose Escalation Study

Abstract A recent prospective randomized trial comparing standard-dose to high-dose melphalan in patients presenting with newly diagnosed AL-amyloidosis showed that oral melphalan-dexamethasone (M-dex) given monthly could be considered the current standard of care, with a median survival of 56 months (Jaccard, N Engl J Med 2007). The use of a combination of lenalidomide and dexamethasone has also been tested in patients with symptomatic AL-amyloidosis. The initial dose of lenalidomide at 25 mg/day was poorly tolerated. However, a 15 mg/day dose regimen was well tolerated and effective, with both hematologic and organ responses (Dispenzieri, Blood 2007 & Sanchorawala, Blood 2007). Combining M-dex with lenalidomide (M-dex-rev) could increase the response rate but the toxicity of this regimen is still unknown. Thus we have initiated a multicenter single-arm open-label phase I/II dose escalation study of lenalidomide administered in combination with M-dex. The primary endpoint was the incidence of dose limiting toxicities (DLT) during the first cycle of lenalidomide at a given dose level in order to determine the maximum tolerated dose (MTD). In addition to melphalan 0.18mg/kg/day from day 1–4 of each 28 day cycle and dexamethasone 40mg/day from day 1– 4 of each 28 day cycle, 3 cohorts of 3 subjects were successively exposed to escalating doses of lenalidomide (5, 10 and 15mg once daily on days 1–21 of a 28 day cycle). DLT was defined using National Cancer Institute (NCI) common toxicity criteria during the first 4 weeks of treatment (one cycle) as the following: at least grade 2 cardiac arrhythmia, at least grade 3 non hematologic toxicity, grade 4 neutropenia lasting >7 days or any other Grade 4 hematologic toxicity, or treatment delay due to toxicity that occurred during the first cycle. No DLT was observed among the first 3 patients treated at 5, 10 and 15 mg lenalidomide/day. 9 additional subjects will be enrolled at 15 mg/day to better define the safety profile and estimate the hematologic and organ response rate. Final results regarding both toxicity and efficacy will be presented during the meeting.

scholarly journals A Safety Study of the Addition of Omacetaxine to the Standard-of-Care Induction Regimen of Cytarabine and Idarubicin in Newly-Diagnosed AML Patients

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5218-5218
Author(s):  
Sonia Christian ◽  
Kelley E. Kozma ◽  
Stephanie Barath ◽  
Ardaman Shergill ◽  
Damiano Rondelli ◽  
...  
Keyword(s):  
High Risk ◽  
Phase I ◽  
Dose Level ◽  
Dose Escalation ◽  
De Novo ◽  
Standard Of Care ◽  
Hematologic Toxicity ◽  
Newly Diagnosed ◽  
Induction Regimen ◽  
Dose Levels

Abstract Background: Omacetaxine mepesuccinate (OM) is a semi-synthetic form of Homoharringtonine (HH), a cephalotaxine alkaloid. OM induces cell apoptosis by inhibiting peptide bond formation during mRNA translation, with rapid loss of short-lived proteins, such as MCL-1, c-MYC, and Cyclin D1 (Lu, J Hematol Oncol. 2014, 7: 2). Notably, cytarabine synergizes with HH in causing apoptosis of leukemia cells in vitro. A phase III RCT in China of 620 patients with de novo AML demonstrated superior CR and 3-yr survival rates upon addition of HH to a standard 2-drug AML induction therapy ('7 + 3'; Jin, Lancet Oncol. 2013, 14:599). Thus, we hypothesized that OM, at an appropriate dose, would similarly enhance the efficacy of a 7 + 3 regimen. OM is FDA-approved for the treatment of TKI-resistant CML. The MTD of 1.25 mg/m2/d SQ for 14 days every 28 days, as determined in a phase I/II CML trial of OM (Quintás-Cardama, Cancer 2007, 109: 248), served as a basis for the dose escalation used in this study. Methods: The primary endpoint of this phase I safety trial was to determine the optimally safe and active dose (OD) of OM when added to a standard 7 + 3 induction regimen, cytarabine and idarubicin. OM was administered SQ q12h d1-7 with cytarabine (100mg/m2 CIV) d1-7 and idarubicin (12mg/m2 IV) d1-3. Four dose levels were tested, starting with OM 0.625 mg/m2 q12h (further dose levels: 1.25, 2.0, 3.0, and 4.2 mg/m2 q12h). All newly diagnosed, untreated de novo or secondary AML patients, aged 18-70y with ECOG PS of 0-3 were eligible for this study. Secondary endpoints included overall response rate (ORR) and overall and event free survival (OS, EFS). Hematologic toxicity (HT) was defined as incomplete hematologic recovery; ANC < 1.0 x 109/L or platelet count < 100 x 109/L present at d49, with the bone marrow documented to be free of leukemic infiltration. Dose escalation was based on the EffTox design (Biometrics 2004, 60:684), a Bayesian adaptive design which considers the trade-off between efficacy and toxicity in determining the OD for Phase II trials. Results: Twenty-two patients, median age 58 (range 25-69) years were enrolled from June 2015 to June 2018. 12 patients (54.5%) had adverse cytogenetics, 6 (27%) intermediate risk, 3 (13.7%) favorable risk and 1 patient's cytogenetic risk was unknown (fibrotic BM). Eight patients demonstrated disease evolution from myelodysplastic syndrome (MDS). Altogether 16 of the 22 patients (73%) were deemed high risk based on cytogenetics or MDS-AML evolution. The EffTox design was implemented until cohort 4 (3 mg/m2 q12h), where 2 of 3 patients experienced a grade 5 non-hematologic toxicity (NHT), resulting in a dose-limiting toxicity (DLT). Since no DLTs were observed in cohort 3, an additional 5 patients were thus enrolled at this dose level to ensure safety. The OD was determined to be the dose level used in cohort 3: OM 2 mg/m2. No HTs were observed in 21 of 22 patients, (one patient not evaluable). The most common non-hematologic treatment emergent adverse events (TEAEs) of any grade were fever (68%), nausea (64%), vomiting (55%), hyperglycemia (41%), diarrhea (41%), mucositis (36%), headache (36%), sinus tachycardia (32%), rash/dermatitis (32%), and abdominal pain (32%). The most prevalent non-hematologic grade 3/4 TEAEs were febrile neutropenia (23%), hypoxia (18%), hyperglycemia (18%), and dyspnea (18%). ORR (CR and CRi) was 45.5%. Median OS was 605 days and EFS was 100 days. Conclusion: In this population with predominantly high-risk AML, the combination of OM with a standard 7 + 3 regimen demonstrates a manageable safety profile with acceptable efficacy. As ~ 25% of patients achieving CR with '7 + 3' do so after a second induction (based on meta-analysis of 6 trials, n = 1980, see Cancer 2010, 116: 5012), the ORR here is comparable to those receiving a single standard of care induction. The results in this high-risk group are therefore promising and warrant further investigation in a phase II trial. At present, we are assessing leukemic blast MCL protein expression in stored pre-treatment samples to determine if this predicts OM efficacy. NCT02440568. Teva has performed a Medical Accuracy Review of this abstract. Figure. Figure. Disclosures Khan: Teva: Speakers Bureau. Patel:Celgene: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Janssen: Honoraria.

Dose Escalation Study To Evaluate Dose Limiting Toxicity (DLT), Maximum Tolerated Dose (MTD) and Safety of Alemtuzumab for Consolidation Therapy in Patients with Chronic Lymphoycytic Leukemia: Phase I/II Trial of the German CLL Study Group (GCLLSG).

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2053-2053 ◽  
Author(s):  
Kirsten Fischer ◽  
Carmen D. Schweighofer ◽  
Matthias Ritgen ◽  
Sebastian Boettcher ◽  
Elena Scharf ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Level ◽  
Dose Escalation ◽  
Partial Remission ◽  
Plasma Concentrations ◽  
Maximum Tolerated Dose ◽  
Lymphocytic Leukemia ◽  
Phase Iii ◽  
Infection Prophylaxis ◽  
Dose Escalation Study

Abstract Introduction: Alemtuzumab has shown considerable activity in both relapsed/refractory chronic lymphocytic leukemia (CLL) and frontline treatment setting. In a prior randomised phase III trial we have demonstrated that consolidation with alemtuzumab significantly improves progression-free survival and the rate of molecular remissions in CLL patients after fludarabine based chemotherapy. However, significant toxicity including severe infections were observed. This ongoing phase I/II trial investigates the maximum tolerated dose (MTD) of alemtuzumab consolidation in patients with CLL after 2nd line chemotherapy. Methods: 12 patients (pts) in complete or partial remission after induction chemotherapy with either fludarabine plus cyclophosphamide (FC) or fludarabine plus cyclphosphamide plus rituximab (FCR) were eligible to receive alemtuzumab consolidation 90 to 150 days after last chemo infusion. Alemtuzumab was administered in 2 different cohorts either intravenously (iv, cohort A) or subcutaneously (sc, cohort B), once weekly for 8 weeks. Dose escalation was started with 10 mg iv/sc and increased in 10 mg intervals per dose level, each dose level including a minimum of 3 pts. All pts received standard premedication and infection prophylaxis. Blood samples were taken to determine pharmacokinetics in week 4 and 8. MRD was evaluated in peripheral blood and bone marrow by 4-colour flow cytometry at week 8 and 3-monthly thereafter. Results: 10 pts (median age 68 years) in complete or partial remission (1 CR, 1 nPR, 8 PR) after FC/FCR were treated with alemtuzumab in cohort A. Due to 2 dose limiting toxicities (DLT) at dose level 2 (20 mg iv, 1 FUO requiring iv antibiotics, 1 exacerbated erythema exsudativum multiforme) the MTD of alemtuzumab was determined at 10 mg iv. In cohort B, so far 2 patients (1 CR, 1 PR) have been treated with 10 mg alemtuzumab sc and no DLT has been observed. Besides the 2 DLT overall toxicity was tolerable in both cohorts with 8 CTC grade III cytopenias reversible in less then 2 weeks, 1 FUO and 2 subclinical CMV reactivations. All infections were successfully treated. After the last dose of alemtuzumab (week 8) the clinical response status of 4 pts converted from PR to CR. Up to a median follow up of 22 months 3 pts presented with PD, 2 of them died due to disease progression. MRD negativity (&lt; 1 × 10E-4) was achieved in 3/10 pts in cohort A and 1/2 pts in cohort B. The median PFS of all pts was 19.9 months. For the majority of patients examined alemtuzumab plasma concentrations in week 4 and 8 showed rapid accumulation with stable levels after administration in the range of 100 to 300 ng/ml. Conclusion: Consolidation with alemtuzumab in CLL pts after 2nd line therapy is safe and able to achieve response improvement including MRD negativity. Dose escalation of alemtuzumab has determined a MTD of 10 mg, if administered intravenously. Ongoing trial activity is attempting to determine the MTD, pharmacokinetic and clinical efficacy of subcutaneous alemtuzumab consolidation.

Combination of Bendamustine, Lenalidomide, and Dexamethasone (BLD) in Patients with Refractory or Relapsed Multiple Myeloma Is Safe and Highly Effective: Results of Phase I/II Open-Label, Dose Escalation Study

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 304-304 ◽  
Author(s):  
Suzanne Lentzsch ◽  
Amy O'Sullivan ◽  
Ryan Kennedy ◽  
Mohammad Abbas ◽  
Navkiranjit Gill ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Level ◽  
Dose Escalation ◽  
Research Funding ◽  
Open Label ◽  
Dose Escalation Study ◽  
Best Response ◽  
Label Dose ◽  
Fast Responses

Abstract Abstract 304 Background: Bendamustine is a bifunctional alkylating agent that is approved for the treatment of chronic lymphocytic leukemia and indolent non-Hodgkin's lymphoma. This first multicenter, phase I/II trial investigated the combination of bendamustine, lenalidomide and dexamethasone (BLD) as a potentially effective treatment option for multiple myeloma (MM) patients, particularly for those with pre-existing or bortezomib-induced neuropathy. Our primary objective was to determine the maximum tolerated dose (MTD) and safety profile of bendamustine and lenalidomide when administered with dexamethasone for patients with relapsed or refractory MM. Methods: We conducted an open-label, dose escalation study (Table 1). Patients were enrolled from June 2008 through February 2011. Eligible patients were aged ≥ 18 years with confirmed, measurable stage II or III MM that was refractory to or progressed after 1 or more prior therapies including lenalidomide. Patients were assigned to their dose levels in a classical 3+3 cohort design. Phase I was to assess the safety and to establish the MTD of the combination treatment. The phase II portion of the study was to assess the overall response rate (ORR) at the MTD. Intravenous bendamustine was given on days 1 and 2, oral lenalidomide on days 1–21, and oral dexamethasone on days 1, 8, 15, and 22 of the 28-day cycle. Treatment was given until plateau of best response as determined by the International Myeloma Working Group uniform response criteria for a maximum of 8 cycles. The study doses were escalated through 3 levels, in a 3+3 dose escalation scheme. The MTD was defined as the dose level at which ≤1 of 6 patients experienced dose-limiting toxicity (DLT) during the first cycle of therapy when the next higher dose level was associated with DLTs in ≥ 2 patients. Primary endpoint was the MTD. After determining the MTD, up to 12 additional patients were enrolled in an MTD expansion arm to better evaluate toxicity and clinical activity. Secondary endpoints included preliminary efficacy, as evidenced by objective response, time to disease progression, and overall survival. Results: 36 patients with a median age of 63 years (range 38 to 80) were enrolled. The median number of prior therapies was 3 with a range of from 2–9; 79% of the patients had prior lenalidomide, 48% had prior thalidomide, and 34% had both. 69% of the patients had a prior autologous stem cell transplant. The MTD was 75 mg/m2 for bendamustine and 10 mg for lenalidomide. DLTs included at dose level 2: 1 grade 4 neutropenia; at dose level 3: 2 grade 4 neutropenias and 1 delayed platelet recovery from grade 3 thrombocytopenia. 25 received at least 2 cycles and were included into the response assessment. A partial response or better was observed in 52% (n=13) of the patients, including 24% (n=6) VGPR. MR was observed in 24% (n=6), SD 16% (n=4), and PD 8% (n=2). BLD induced fast responses with a time to best response of 1.6 months (range 0.7–7.4). The response was independent of prior exposure to lenalidomide evidenced by the fact that 84% of patients with VGPR/PR had prior treatment with lenalidomide. The median follow up for patients at risk of progression is 8 months (range 4–13). The estimated median progression free survival (PFS) is 4.4 months (95% CI (3.4, 9.2). 4 patients have died and the median follow up for patients who are still alive is 13 months (range 6–33). The median OS survival has not been reached yet. We did not observe any unanticipated DLTs. The only grade 4 adverse events for all patients for all cycles included 24.1% neutropenia and 7% thrombocytopenia. No infection was associated with the neutropenia and all AE resolved successfully. Conclusions: This is the first phase I/II trial testing bendamustine, lenalidomide and dexamethasone in combination for relapsed and refractory MM. This regimen is safe and well tolerated even in older patients up to 80 years. Based on the mainly myelosuppressive side effects, concomitant treatment with filgastrim is recommended. This regimen induced fast responses and high response rates even in heavily pretreated MM patients. The high responses were also achieved in patients with prior exposure to lenalidomide suggesting that BLD overcomes resistance to lenalidomide and is a highly active regimen. Disclosures: Lentzsch: Celgene Corp: Consultancy, Research Funding; Onyx: Consultancy; Genzyme: Consultancy; prIME Oncology: Honoraria; Imedex: Honoraria; Clinical Care Options: Honoraria. Burt:Celgene Corp: Honoraria, Speakers Bureau; Cephalon: Honoraria, Speakers Bureau. Roodman:Amgen: Consultancy; Millennium Pharmaceuticals: Consultancy. Agha:Novartis: Consultancy. Zonder:Millennium: Consultancy, Research Funding, Speakers Bureau; Celgene: Speakers Bureau; Medtronics: Honoraria; Amgen: Consultancy.

Phase I study of ABT-751 in combination with CAPIRI (capecitabine and irinotecan) and bevacizumab in patients with advanced colorectal cancer

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 13553-13553
Author(s):  
W. A. Messersmith ◽  
M. A. Rudek ◽  
D. Laheru ◽  
M. Zhao ◽  
P. He ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Combination Therapy ◽  
Phase I ◽  
Dose Level ◽  
Dose Escalation ◽  
Advanced Colorectal Cancer ◽  
Standard Of Care ◽  
Maximum Tolerated Dose ◽  
Total Daily Dose ◽  
Dose Escalation Study

13553 Background: ABT-751 (A) is an orally (PO) bioavailable sulfonamide with antimitotic properties. We are performing a non-randomized phase I/II dose-escalation study of A in combination with capecitabine (C), irinotecan (I) and bevacizumab (B) to define the maximum tolerated dose (MTD), dose-limiting toxicity (DLT), and pharmacokinetics (PK) in patients with advanced colorectal cancer (1st or 2nd line). Methods: Patients are treated with A QD for 7d (lead-in) and then begin 21-d cycles of treatment with A (QD) and C (BID) d1–14 PO, I d1 IV, and B d1 IV. Dose escalation started at dose level (DL) 1 at A 150 mg, I 200 mg/m2, and C 1600 mg/m2 (total daily dose) and escalated to full dose CAPIRI (I 250 mg/m2, and C 2000 mg/m2) for DL2. B was then added as standard of care at 7.5 mg/kg for DL2b (and later, DL1b). Blood samples were collected for pharmacogenomics (PG), pharmacodynamics (PD), steady-state PK of A and A metabolites when administered alone or in combination with C, I, and B, and PK of I and I metabolites. Serial dynamic contrast MRI’s, before and after the ABT-751 monotherapy lead-in period, are being performed in a subset of subjects. Results: Eight patients have been treated at dose levels 1 (3), 2 (2), and 2b (3). One patient on DL2 experienced g3 transaminitis and another on DL2b had F&N which were dose-limiting. Dose level 1 is being expanded to 6 patients, now with B (DL1b). Other g3/4 toxicities have included g4 neutropenia (1 subject DL2, 1 DL2b). The formation of A glucuronide appears decreased during combination therapy (see table). I PK, PD, and PG samples were collected and analysis is pending. Of 8 subjects, there have been 4 PD and 4 SD after 2 cycles. Conclusions: The combination therapy of A 150 mg and 20% dose-reduced CAPIRI appears well-tolerated. Patient accrual continues at DL1b. [Table: see text] No significant financial relationships to disclose.

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.

A phase I, dose-escalation and expansion study of TQ-B3139, a novel ALK TKI, in Chinese ALK or ROS1 positive advanced non-small cell lung cancer (NSCLC).

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 9585-9585
Author(s):  
Yuxiang Ma ◽  
Nong Yang ◽  
Su Li ◽  
Hongyun Zhao ◽  
Liu Li ◽  
...  
Keyword(s):  
Brain Metastasis ◽  
Phase I ◽  
Dose Level ◽  
Dose Escalation ◽  
Objective Response ◽  
Phase Iii ◽  
Alk Inhibitor ◽  
Grade 3 ◽  
Recommended Phase Ii Dose ◽  
Nsclc Patients

9585 Background: TQ-B3139 is a novel ALK inhibitor with activity 3-7 folds higher than Crizotinib against a broad range of ALK mutations. This phase I study (NCT03099330) is to investigate the safety, and determine the recommended phase II dose (RP2D), and pharmacokinetic (PK), clinical efficacy of TQ-B3139 in Chinese NSCLC patients. Methods: Patients with advanced NSCLC and failed at least one systemic anti-cancer treatment were enrolled. TQ-B3139 was administered orally from 50mg~100mg qd and 200, 300, 400, 500, 600 and 800mg bid, using a PK-guided modified Fibonacci 3+3 dose escalation design. The dose-escalation evaluated patients in 28-day cycles, dose limited toxicities (DLTs) was observed at first cycle. Dose-expansion phase started at dose level which objective response occurs. Treatment was continued until disease progression, death or unacceptable toxicity. Results: Between July 2017 and May 2019, totally 63 patients (59 ALK+, 4 ROS1+) were enrolled. Sixteen patients had prior ALK inhibitor therapy (11 Crizotinib, 5 Ensartinib), and 23 (36.5%) with baseline brain metastasis. Totally, 62 (98.4%) patients experienced treatment-related adverse events (TRAEs), grade 3-4 TRAEs were observed in 21 (33.3%) patients. One DLT occurred in the 800mg bid dose cohort (grade 3 nausea and vomiting). Top 3 common TRAEs were nausea (all grade 87.3%; grade 3-4 3.2%), diarrhea (84.1%, 6.4%), transaminase elevation (65.1%, 4.8%). AUC and Ctrough at steady state increased proportionally from 200mg to 600mg bid. Absorption saturation was observed in 800mg bid. Base on the safety and PK results, PR2D was decided at 600mg bid. Overall ORR was 73.0% (2 CR, 44 PR); DCR was 85.7% (8 SD). Objective response was observed from dose level 200mg bid cohort, ORR and DCR at ≥200mg bid was 78.0% and 89.8%. For ALK TKI-naïve and -resistant patients, the ORR was 78.7% (37/47) and 56.3% (9/16) respectively. For patients with measurable baseline brain metastasis, the ORR for brain lesions was 80.0% (8/10). At data cut-off (23 Jan 2020), 32 events (50.8%) occurred, the median PFS for all patients was 12.1 months (95%CI 8.5-15.6), for patients at ≥200mg bid dose was 12.2 months. The median PFS was not reached for -naive patients (6 months PFS rate 74.5%, 95%CI 68.1-80.9), and 5.6months (95%CI 1.6-9.5) for ALK TKI-resistant patients. Conclusions: TQ-B3139 was well tolerated in Chinese NSCLC patients with high antitumor activity. RP2D was established at 600mg bid. A randomized phase III trial of TQ-B3139 versus Crizotinib in advanced ALK-TKI naïve NSCLC patients is underway. Clinical trial information: NCT03099330 .

Can polymetastatic disease be arrested using SABR? A dosimetric analysis to inform development of a phase I trial.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e21567-e21567
Author(s):  
Mark Thomas Corkum ◽  
Hatim Fakir ◽  
David A. Palma ◽  
Timothy K. Nguyen ◽  
Glenn Bauman
Keyword(s):  
Clinical Trial ◽  
Phase I ◽  
Dose Level ◽  
Phase I Trial ◽  
The Body ◽  
Phase Iii ◽  
Whole Body ◽  
Stereotactic Ablative Radiotherapy ◽  
Test Cases ◽  
Dose Escalation Study

e21567 Background: Phase II randomized trials suggest that stereotactic ablative radiotherapy (SABR) improves progression-free and overall survival in patients with oligometastatic cancer, with phase III trials currently testing SABR in up to 10 metastases. Whether SABR could provide similar benefits in polymetastatic disease ( > 10 metastases) is unknown. A critical first step is to determine the feasibility of planning SABR for a large number of metastases throughout the body while maintaining acceptable organ at risk (OAR) doses. Therefore, we sought to evaluate the dosimetric feasibility of using SABR in polymetastatic disease ( > 10 sites) while adhering to OAR constraints to be used in a phase I trial (ARREST). Methods: Five craniospinal CT simulations were utilized to retrospectively contour 24 (n = 2), 30 (n = 2) and 50 (n = 1) tumour targets not present on the initial scan. Standard PTV margins were added based on institutional immobilization practices. OAR constraints from published clinical trial protocols were used. Radiotherapy plans for the highest dose level in our planned phase I trial (30Gy in 5 fractions) were created utilizing a minimum number of isocentres. Plans were created using Raystation (RaySearch Laboratories, Stockholm, Sweden) for delivery on linear accelerators using volumetric modulated arc therapy. Results: The gross tumour volumes (GTVs) ranged from 134.8– 184.2cm3 in our five test cases. The first two cases with 24 GTVs have been planned and were deemed to be clinically acceptable. PTV volumes were 483.0cm3 and 417.4cm3, utilizing five and six isocentres for treatment respectively. Median PTV D95 was 29.7Gy and 29.0Gy, whole body V10 was 21.2% and 17.4%, and V5 was 41.8% and 44.8%. All OAR goals were met, though low-dose conformality was less than traditional SABR treatment plans (R100 of 1.04 and 0.93; R50 of 9.90 and 6.98, respectively). The remainder of the test cases will be presented. Conclusions: In our test cases, planning SABR in polymetastatic disease appears dosimetrically feasible. Our phase I clinical trial (ARREST) is under development, which will evaluate the feasibility and toxicity of delivering SABR in polymetastatic disease in a 3+3 dose escalation study. The starting dose level will be 12Gy in 2 weekly fractions, escalating the dose by adding 6Gy weekly until our target dose of 30Gy in 5 weekly fractions. Our study population will include > 10 sites of disease, all tumour types, and patients must have exhausted standard lines of systemic therapy.

scholarly journals An Open-Label, Phase Ib Study of Duvelisib (IPI-145) in Combination with Bendamustine, Rituximab or Bendamustine/Rituximab in Select Subjects with Lymphoma or Chronic Lymphocytic Leukemia

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4422-4422 ◽  
Author(s):  
Ian Flinn ◽  
Manish R. Patel ◽  
Michael B Maris ◽  
Jeffrey Matous ◽  
Mohamad Cherry ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Febrile Neutropenia ◽  
Phase I ◽  
Dose Escalation ◽  
Research Funding ◽  
Treatment Delay ◽  
Lymphocytic Leukemia ◽  
Open Label ◽  
Grade 3

Abstract Background: Duvelisib is a potent inhibitor of the δ and γ isoforms of phosphoinositide-3-kinase (PI3K) being developed as a potential therapeutic in hematologic malignancies including B and T cell lymphoma and chronic lymphocytic leukemia (CLL). In a phase I study of single agent duvelisib (D), ORR of 52% was seen in pts with indolent non-Hodgkin’s lymphoma (iNHL) and 47% in CLL. Bendamustine (B), rituximab (R), and their combination have demonstrated proven activity in iNHL and CLL. Combining duvelisib with either bendamustine or rituximab alone or in combination with each other may improve response rates and the durability of remission. The goal of this Phase 1b, open-label, three-arm, non-randomized, dose escalating, safety and tolerability trial is to characterize the safety, maximum tolerated dose (MTD) and preliminary efficacy profile of duvelisib given in combination with rituximab (Arm 1-DR), bendamustine plus rituximab (Arm 2-DBR) or bendamustine (Arm 3-DB) in subjects with select relapsed/refractory lymphoma or CLL. Methods: Pts had relapsed CLL or NHL, ECOG performance status (PS) ≤2, and adequate organ function. The subject population during dose escalation was limited to relapsed NHL. During the dose expansion phase, each treatment arm enrolled to population specific cohorts to continue to assess efficacy. Arm 1 (DR) received rituximab 375 mg/m2 IV weekly for 2, 28 day cycles plus duvelisib PO BID up to 12 cycles. Arm 2 (DBR)received rituximab 375 mg/m2 IV weekly for 2, 28 day cycles, bendamustine 90 mg/m2 IV on Days 1 and 2 of the first six cycles plus duvelisib PO BID up to 12 cycles. Arm 3 (DB) received bendamustine 120 mg/m2 IV on Days 1 and 2 of the first six cycles plus duvelisib PO BID up to 12 cycles. Three different dose levels of duvelisib were explored, 25, 50, and 75 mg PO BID. DLTs were defined as: febrile neutropenia, G4 neutropenia ≥7 days, G4 thrombocytopenia ≥ 7 days or G3 thrombocytopenia with bleeding, Grade 4 AST/ALT, Grade 2 hyperbilirubinemia ≥7 days, ≥ Grade 3 non-hematologic toxicity ≥7 days (excluding alopecia), Treatment delay of ≥7 days due to unresolved toxicity that prevents re-dosing, hepatocellular injury (defined as ALT>2 x ULN and (ALT/ULN)/(ALP/ULN) >5) and bilirubin >2 x ULN or jaundice ± alkaline phosphatase <2 x ULN. Patients were evaluated for response every 3 cycles according to specific criteria for their disease. Results: Between August 2013 and May 2014, 32 pts, median age 66 years (44-78) were enrolled to the study, 12 NHL pts on the dose escalation portion and 20 pts on dose expansion (13 CLL, 7 NHL). Patients had a median of 4 prior therapies (1-11). In arms 1 (DR) and 2 (DBR), no dose limiting toxicities were seen at the highest dose level of duvelisib (75 mg bid). In arm 3 (DB) in which a higher dose of bendamustine is used 1 pt developed a DLT at the 50 mg BID dose level of duvelisib (febrile neutropenia, neutropenia ≥ 7 days, thrombocytopenia ≥ 7 days, and liver toxicities which resulted in a treatment delay of ≥ 7 days). Dose escalation continues in this arm as the MTD has not reached. Patients on the dose expansion portion of the study are receiving duvelisib at 25 mg BID due to emerging data of duvelisib monotherapy showing no advantage in doses greater than 25 mg BID in these histologies. The AE profile is consistent with the toxicities of the single agents. The most common AEs > grade 3 were neutropenia (28% overall; [Arm 1 (DR), 27%]; [Arm 2 (DBR), 38%]), and rash (16% overall; [Arm 1, 14%]; [Arm 2, 25%]). Grade 3 or higher AST/ALT increases were seen in 2 out of 12 patients on Arm 1, 2 out of 8 patients on Arm 2 and no patients on Arm 3. There have been 2 deaths (cardiac arrest and pneumonia), both on Arm 1. Twenty one pts were evaluable for response with an ORR of 81% (10% CR, 71% PR, 14% SD and 5% PD). With a median follow up of 4.0 months, time to event analyses are immature. However, Kaplan-Meier estimate of PFS at 3 months is 87%. PK analysis is consistent with the monotherapy Phase I trial of duvelisib. Conclusions: Initial early analysis of duvelisib administered in combination with bendamustine and rituximab suggests these combinations to be generally well-tolerated with encouraging. Further follow-up is required to better characterize response rates and durability of remissions. Disclosures Flinn: Infinity Pharmaceuticals: Research Funding. Matous:Infinity Pharmaceuticals: Research Funding.

Dual epidermal growth factor receptor (EGFR) inhibition: Phase I study combining cetuximab (C225) and erlotinib (E) in advanced solid tumors

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 3552-3552
Author(s):  
R. Sangha ◽  
C. Ho ◽  
L. Beckett ◽  
D. H. Lau ◽  
P. N. Lara ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Dose Level ◽  
Phase Ii ◽  
Dose Escalation ◽  
Gene Copy ◽  
Hematologic Toxicity ◽  
Advanced Solid Tumors ◽  
Egfr Inhibition ◽  
Biomarker Analysis

3552 Background: The EGFR pathway is implicated in lung tumorigenesis by aberrantly regulating cell proliferation, apoptosis, and invasion. Maximal blockade of the EGFR can be achieved by dually inhibiting the extracellular and intracellular domain with the monoclonal antibody C225 and the tyrosine kinase inhibitor, E. Given preclinical synergy of C225 and E, we hypothesized this combination would be feasible and result in improved therapeutic benefit. Methods: Patients (pts) with advanced solid tumors were enrolled using a standard phase I dose escalation design. C225 was administered IV weekly, with no loading dose, and E given orally daily on a 28-day cycle. Four dose levels were studied: C225 150 mg/m2, E 100 mg; C225 200 mg/m2, E 100 mg; C225 250 mg/m2, E 100 mg; and C225 250 mg/m2, E 150 mg. Dose limiting toxicity (DLT) was defined as: grade (Gr) 4 platelets, Gr 3 platelets with bleeding, febrile neutropenia, ≥ Gr 3 ANC with documented infection, or clinically significant > Gr 3 non-hematologic toxicity. Gr 3 rash based solely on pain or Gr 3 hypersensitivity infusion reactions were not considered DLTs. Results: 18 pts were treated: 13 NSCLC, 3 H&N, 1 pancreas, and 1 invasive thymoma. Characteristics: Age range 41–80, median 62.5; Gender: 7 M; ECOG PS ≤1 = 17; Prior chemo ≤1 = 10. Planned dose escalation was completed without reaching the MTD. The highest dose level was expanded to 6 pts. A single DLT for Gr 3 diarrhea was observed at the second dose level (C225 200 mg/m2, E 100 mg). Gr 3/4 toxicities were: lymphopenia (3), acneiform rash (3), nausea/vomiting (3), pruritis (1), fatigue (1), diarrhea (1), confusion (1), hypomagnesemia (1), hypocalcemia (1), hyponatremia (1), hyperkalemia (1), and anemia (1). Of 13 evaluable pts, 1 PR (NSCLC) and 4 with SD (2 NSCLC, 2 H&N). Median cycles: 2 (1–14) with one NSCLC pt on therapy for 8 cycles and one H&N pt receiving 14 cycles. Biomarker analysis of EGFR polymorphisms, gene copy number via FISH, and protein expression will be presented, along with the mutation status of EGFR and KRAS. Conclusions: 1) Dual EGFR inhibition with C225 250 mg/m2 weekly and E 150 mg daily is feasible, well tolerated, and the recommended phase II dose. 2) Efficacy of this combination in NSCLC is being evaluated in a phase II trial. [Table: see text]

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