An open-label, first-in-human, phase I trial of the safety and efficacy of daily PCLX-001.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. TPS3656-TPS3656
Author(s):  
Randeep S. Sangha ◽  
Laurie Helen Sehn ◽  
John Kuruvilla ◽  
Michael Weickert ◽  
John Robert Mackey ◽  
...  
Keyword(s):  
Phase I ◽  
B Cell ◽  
Cell Lines ◽  
Dose Level ◽  
Cancer Cell ◽  
Dose Escalation ◽  
Solid Tumor ◽  
Single Agent ◽  
Open Label ◽  
Recommended Phase Ii Dose

TPS3656 Background: Myristoylation regulates numerous membrane-bound signal transduction pathways important in cancer biology. This modification is catalyzed by N-myristoyltransferases 1 and 2 (NMT1 and NMT2). PCLX-001 is an oral small molecule with high affinity for both NMT proteins (IC50 of 5nM and 8nM, respectively) with high bioavailability and drug-like pharmacokinetic properties. In ex vivo sensitivity screening cell lines of hematologic cancer origin were exquisitely sensitive to PCLX-001, although high sensitivities and cell killing were also seen in some solid tumor lines derived from lung, pancreas, breast, colon, and bladder carcinomas. PCLX-001 demonstrated strong preclinical single-agent antitumor activity and tolerability in vivo in subcutaneous tumor xenograft models derived from lymphoma cell lines, lung cancer cell lines, a breast cancer cell line, as well as in a patient derived xenograft model from a patient with refractory DLBCL. The primary objective of this study is to determine the MTD and/or recommended phase II dose, safety, tolerability, and pharmacokinetics of PCLX-001 as a single agent, in patients with refractory lymphomas and advanced solid tumors. The secondary objective of the study is to evaluate the preliminary single agent anti-tumor activity of PCLX-001 in the patient populations studied. Methods: This is a multicenter, open-label, phase I dose-escalation study of oral PCLX-001 comprised of two parts (dose escalation and dose expansion). Eligible patients will have: histologically-confirmed advanced solid tumor or B-cell lymphomas who have failed prior therapy and/or are not eligible for therapies; ages ≥ 18 years; adequate organ function; life expectancy of at least 12 weeks; and measurable disease. Part A (dose-escalation) patients will be accrued in cohorts of 3 to 6 patients to each dose level, starting at 20 mg daily on a 28 day cycle. Dose escalation will follow a modified Fibonacci design such that the magnitude of escalation decreases as the dose level nears the human equivalent dose of the highest non-severely toxic dose in dogs and then escalate at 1.4 times the previous dose. Dose escalation and determination of the maximum tolerated dose will be based on the occurrence of dose limiting toxicities in cycle 1. Part B will have two single agent expansion cohorts (n = 20 each) in advanced solid malignancies and relapsed/refractory B-cell lymphoma, to determine the preliminary clinical activity of PCLX-001 to determine the recommended phase II dose. The first patient on study is planned for Q3 2020.

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]

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 .

A phase I study of temozolomide (TMZ) and RAD001 in patients (pts) with glioblastoma multiforme (GBM)

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 2036-2036
Author(s):  
W. P. Mason ◽  
M. MacNeil ◽  
J. Easaw ◽  
L. McIntosh ◽  
Z. Lwin ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Level ◽  
Single Agent ◽  
Maximum Tolerated Dose ◽  
Newly Diagnosed ◽  
Mtor Inhibition ◽  
Daily Schedule ◽  
Starting Dose ◽  
Mtor Protein ◽  
Recommended Phase Ii Dose

2036 Background: The mTOR protein kinase is a critical step in the PI3K/Akt/PKB signaling pathway. RAD001 exerts antiproliferative and antiangiogenic effects by mTOR inhibition. This phase I trial was designed to determine the maximum tolerated dose(s) (MTD) and recommended phase II dose(s) of RAD001 in combination with TMZ in patients with GBM. Patients receiving enzyme inducing anti-epileptic drugs (EIAEDs) and those not receiving EIAEDs (NEIAEDs) were studied separately. Methods: Enrollment was restricted to pts with proven GBM, either newly diagnosed following completion of radiotherapy with concurrent TMZ, or at first progression. TMZ was administered at a starting dose of 150 mg/m2/d for 5 days every 28 days, and RAD001 was administered continuously at a starting dose of 2.5 mg orally on a daily schedule starting on day 2 of cycle 1 in 28-day cycles (maximum 10 mg daily unless PK interaction shown). Response was evaluated every 2 cycles. Pharmacokinetics (PK) of TMZ and RAD001 were determined during cycle 1. Results: To date, 16 NEIAEDs and 9 EIAEDs pts have been enrolled and received 79 and 58 cycles respectively. The majority of pts (20/23) were newly diagnosed. In the NEIAEDs group at dose level 2 (RAD001 2.5 mg, TMZ 200 mg/m2) 3 of 4 pts had cycle 2 delays and dose reduction of TMZ because of myelosuppression (neutropenia 2 pts, neutropenia and thrombocytopenia, 1 pt), so further escalation of only RAD001 was undertaken, while fixing TMZ at 150 mg/m2. RAD001 at 10 mg daily with TMZ 150 mg/m2/day has been well tolerated in the NEIAEDs cohort without DLTs; RAD001 PK at this dose level have been comparable to historical single agent RAD001 PK (AUC at steady state is 602 ng*hr/mL in our study vs. 536 ng*hr/mL historical data), so no further escalation is planned. Enrollment in the EIAEDs cohort has been accelerated to 10 mg RAD001 with TMZ 150 mg/m2 because no additional DLTs have been observed in the EIAEDs cohort. Escalation beyond this dose will only take place if supported by evidence of reduced exposure of RAD001 or TMZ when PK results are available. Conclusions: RAD001 at a daily dose of 10mg can safely be combined with TMZ at 150 mg/m2/d and is the recommended dose for GBM pts receiving NEIAEDs. EIAED pts are being enrolled at this dose level; further escalation in this group will depend on PK data. [Table: see text]

A phase I trial of the oral hedgehog inhibitor taladegib (LY2940680) in combination with weekly paclitaxel in patients with advanced, solid tumours.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 2594-2594
Author(s):  
Rosalind Margaret Glasspool ◽  
Sarah Patricia Blagden ◽  
Michelle Lockley ◽  
James Paul ◽  
Carol Hopkins ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Level ◽  
Dose Escalation ◽  
Single Agent ◽  
Primary Objective ◽  
Solid Tumours ◽  
Muscle Cramp ◽  
Weekly Paclitaxel ◽  
Level 1 ◽  
Level 2

2594 Background: Aberrant Hedgehog (Hh) signaling is implicated in carcinogenesis and is associated with poor prognosis in multiple tumours types. Hh inhibitors increase sensitivity to paclitaxel in taxane-resistant cell lines. Taladegib is an orally bioavailable, potent inhibitor of Smoothened, a key Hh pathway component, with activity in basal cell carcinoma. The single agent recommended dose is 400mg od. We present the dose escalation phase of a phase I study of weekly paclitaxel with oral taladegib. Methods: Primary objective: determine the dose limiting toxicity (DLT) and maximum tolerated dose (MTD) of taladegib on a continuous oral daily dosing regimen in combination with paclitaxel (80mg/m2, iv, day 1, 8 and 15 q 28) in patients with advanced solid cancers. Secondary objectives: assess the safety and tolerability, determine the recommended phase II dose (RP2D), and evaluate the pharmacokinetics of taladegib and paclitaxel. Exploratory objective: assess preliminary efficacy. A standard 3 + 3 dose escalation design was used. All patients received up to 6 cycles of paclitaxel. In addition, successive cohorts received continuous oral taladegib continued until progression or unacceptable toxicity as follows: dose level 1: 100mg od; 2: 200mg od; 3: 400mg od. Results: No DLTs were seen at dose level 1 or in the first 3 patients at dose level 2. 3 DLTs of grade 2 neuropathy were seen at dose level 3 (400mg taladegib); therefore, dose level 2 was expanded to 6 patients. No DLT was seen in the fourth patient and 2 additional patients have started treatment. After the DLT period 2 patients developed G2 and 4 developed G1 neuropathy. Other non DLT, drug-related G3 toxicities: uncomplicated neutropenia x2, muscle cramp x1 and fatigue x1. To date, 3 patients have had partial responses. Conclusions: The combination of daily oral taladegib and weekly paclitaxel is feasible. DLT of G2 neuropathy was seen at 400mg. Promising activity has been seen in solid tumours. A dose expansion cohort is due to commence in high grade ovarian carcinoma. ISRCTN No:ISRCTN15903698 Eudract Ref:2014-004695-37 Funded by Cancer Research UK C8361/A18775 and Ignyta. Sponsored by NHS Greater Glasgow and Clyde. Clinical trial information: ISRCTN15903698.

The Use of DT388-IL3 Fusion Protein in Patients with Refractory Acute Myeloid Leukemia(AML).

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4513-4513
Author(s):  
Debashish Misra ◽  
Arthur Frankel ◽  
Philip Hall ◽  
Tie Fu Liu ◽  
Jennifer Black ◽  
...  
Keyword(s):  
Fusion Protein ◽  
Phase I ◽  
Cell Lines ◽  
Dose Level ◽  
Dose Escalation ◽  
Preliminary Data ◽  
Phase I Trial ◽  
Progression Of Disease ◽  
Post Infusion ◽  
Ongoing Phase

Abstract Background: Although complete remission rates for AML are near 70% with combination induction and consolidation chemotherapy, most patients will relapse and die from the disease or treatment complications. New agents with unique mechanisms are needed. One such class of therapeutics are fusion proteins consisting of protein synthesis inactivating peptide toxins fused to tumor cell selective ligands. DT388-IL3 is one such fusion protein. Rationale: In preclinical studies, DT388-IL3 was cytotoxic to the IL3 receptor expressing leukemia cell lines but not toxic to IL3 receptor negative cell lines. This agent was less toxic to normal progenitors and not toxic to early hematopoietic stem cells. The majority of AML progenitors overexpress IL3 receptors. Animal model work in mice bearing human leukemia cells has demonstrated anti-leukemia efficacy which is dose dependent with this agent. Toxicities in monkeys include vascular leak syndrome and pancytopenia observed only at the highest doses. The MTD in monkeys was estimated at 60mcg/kg/day. We report preliminary data on the use of DT388-IL3 fusion protein in humans from an ongoing phase I trial. Pharmacokinetics; clinical and immune response to this novel fusion protein are also being followed. Patients and Methods: Patients with refractory AML were eligible. The first dose level was qd M-W-F X six doses of DT388-IL3 at 4mcg/kg/day with dose escalation planned for subsequent patients. Patients with progression of disease or unacceptable study drug toxicity were to be removed from the study. Toxicity was graded according to NCI CTCAE version 3.0. Three patients have been treated with DT388-IL3. Serum samples were collected and will be assayed for anti-DT388-IL3 antibodies prior to and after treatment. Blood samples were obtained to measure circulating levels of active DT388-IL3 and its half life. Patient blasts were also collected prior to treatment for later analysis of expression of IL3 receptors. Result: Two patients tolerated the treatment schedule(of six doses) without any significant toxicities. Mild fever, headaches, nausea were noted. Both of these patients had progression of disease-one during treatment and one on day 15 bone marrow biospy. The above mentioned patients died secondary to disease complications at 2 weeks and 18 weeks after their last dose of the study agent respectively. DT388-IL3 levels on these two patients post infusion were below the the reliable detectable limits of the assay. The third patient became febrile and hypotensive after the first dose. The hypotension persisted and she did not receive any further doses. This patient is alive 5 weeks later with supportive care alone. DT388-IL3 levels following this patient’s dose are as follows: 2min post infusion 34.3ng/ml, 30min post infusion 1.9ng/ml, 60min post infusion 0.075ng/ml, 120min post infusion 0.003ng/ml, 240min post infusion undetectable. Conclusion: Preclinical/animal studies suggest that DT388-IL3 has anti-leukemia efficacy. Preliminary data from our ongoing phase I trial reveals minimal study agent related toxicity and no life threatening complications at this first dose level. Dose escalation is planned as per protocol.

Open-Label, Prospective, Multicentre, Phase I/II Study of AOP2014, a Novel PEG-Proline-Interferon Alpha-2b in Patients with Polycythemia Vera: Update from an Ongoing Study

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1747-1747
Author(s):  
Heinz Gisslinger ◽  
Robert Kralovics ◽  
Renate Schoder ◽  
Bettina Gisslinger ◽  
Veronika Buxhofer-Ausch ◽  
...  
Keyword(s):  
Platelet Count ◽  
Phase I ◽  
Polycythemia Vera ◽  
Dose Level ◽  
Dose Escalation ◽  
Research Funding ◽  
Study Entry ◽  
Molecular Response ◽  
Open Label ◽  
Multicentre Phase

Abstract Abstract 1747 Background. IFN-alpha (IFN) is reported to induce molecular response in patients with chronic myeloproliferative neoplasms and may therefore improve survival. However, the use of conventional and pegylated IFNs is limited by toxicity, leading to treatment withdrawals in a substantial proportion of patients. In polycythemia vera (PV), recently published phase II data indicate occurence of grade 3 and 4 toxicities in 20%, and toxicity-related discontinuations in 22–24% of patients administered once weekly with pegylated IFNs. Results from large-scale randomized studies of IFNs in PV are not available. AOP2014 is a next generation long-acting IFNa-2b, consisting predominantly of only one isoform as opposed to other commercially available pegylated interferons. AOP2014 is expected to have pharmacokinetic and pharmacodynamic profiles which may allow a reduced dosing frequency compared to other pegylated IFNs, potentially leading to improved tolerability, better compliance, and, finally, favourable long-term treatment outcomes. Study design. This is an open-label, prospective, multicentre, phase I/II dose escalation study of AOP2014 to determine the maximum tolerated dose (MTD), safety and efficacy in PV. Inclusion criteria are: age ≥18 years, confirmed diagnosis of PV (WHO, 2008, or the PSVG plus JAK2 positivity). Both newly diagnosed and pre-treated (cytoreduction) patients are eligible; hydroxyurea (HU) is allowed until the first application of AOP2014. If abnormally elevated prior to entry, sustained hematocrit (Hct) ≤45% is to be achieved by phlebotomy prior to the first administration. 3+3 dose escalation with cohort extension after MTD definition is being utilized. Intra-patient dose escalation to the dose level, previously established to be safe, is encouraged. MTD is defined as the highest dose level at which no more than 1 of 6 subjects experience a DLT during the first treatment period (2 weeks). Complete hematological response (CR) is defined by Hct <45%, platelet count ≤400*109/L, WBC count ≤10*109/L, normal spleen size, and absence of thromboembolic events. Partial response (PR) is defined as haematocrit <45% without phlebotomy but with persistent splenomegaly or elevated (>400*109/L) platelet count, or reduction of phlebotomy requirements by at least 50%. Evaluation of toxicities and JAK2 allele burden quantication will be performed. Results. 20 patients have been included to date, M/F ratio was 16/4, median age 58 years (range 44–83). Median time from diagnosis to inclusion was 19 months (range 0–170). 9 patients were pre-treated with HU prior to study entry. Median number of phlebotomies in the past 3 months prior to inclusion was 1 (range 0–4), a total of 13 patients were regularly phlebotomized at least once in three months prior to study entry. Six patients had a history of thrombotic complications. Median Hct at baseline was 46% in males (range 46–52) and 42% in females (range 41–43). Median WBC and platelet counts were 11.3*109/L (range 4.7–17.8) and 366*109/L (range 148–1016), respectively. Twelve patients (60%) had splenomegaly. Dose levels of 50, 100, 150, 225, 300, 360 and 450 microgramm once in two weeks were investigated. The median reported treatment duration is 24 weeks (range 0–33). After 10 weeks of treatment (14 evaluable patients), 64% of patients had hematological response (2 CR; 7 PR), one patient needed to be phlebotomized. At 18 weeks (9 evaluable patients), 1 patient had CR and 4 – PR, overall response (CR+PR) was 56%; at 28 weeks (8 evaluable patients), 1 patient had CR and 5 PR, overall response was 63%. The only evaluable patient at week 34 had CR. Starting from week 18, no patient required phlebotomy. Mainly grade 1 and 2 adverse events were reported. Administration site reactions developed in 11 patients, all of mild intensity and recovered within 72h. The most frequent adverse reactions were muscle and joint pain and gastrointestinal toxicities (12 and 6 patients, respectively). Fever and depression were observed in 5 and 2 patients, respectively. Drug-related adverse event (depression) was the reason of treatment discontinuation in one patient. Molecular response data are still undergoing evaluation. Conclusion. Response rate of above 60% at six month already observed in the phase I dose finding part suggests that AOP2014 has promising efficacy and good tolerability profile in PV. Updated results will be presented as the trial progresses. Disclosures: Gisslinger: AOP Orphan Pharmaceuticals AG: Research Funding, Speakers Bureau; Novartis: Speakers Bureau; Celgene Austria: Research Funding, Speakers Bureau. Kralovics:(7) AOP Orphan Pharmaceuticals AG: Research Funding. Schoder:AOP Orphan Pharmaceuticals AG: Research Funding. Gisslinger:AOP Orphan Pharmaceuticals AG: Research Funding. Buxhofer-Ausch:AOP Orphan Pharmaceuticals AG: Research Funding. Strecker:AOP Orphan Pharmaceuticals AG: Research Funding. Wolf:AOP Orphan Pharmaceuticals AG: Research Funding. Willenbacher:AOP Orphan Pharmaceuticals AG: Research Funding. Greil:AOP Orphan Pharmaceuticals AG: Research Funding. Egle:AOP Orphan Pharmaceuticals AG: Research Funding. Melchardt:AOP Orphan Pharmaceuticals AG: Research Funding. Burgstaller:AOP Orphan Pharmaceuticals AG: Research Funding. Tarmann:AOP Orphan Pharmaceuticals AG: Employment. Wachter:AOP Orphan Pharmaceuticals AG: Employment. Zahriychuk:AOP Orphan Pharmaceuticals AG: Employment. Thaler:AOP Orphan Pharmaceuticals AG: Research Funding.

scholarly journals Updated Results of a Phase I Study of Ibrutinib and Lenalidomide in Patients with Relapsed and Refractory B-Cell Non-Hodgkin's Lymphoma

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3983-3983 ◽  
Author(s):  
Beth A Christian ◽  
John G. Kuruvilla ◽  
Sonali M. Smith ◽  
Pierluigi Porcu ◽  
Kami J. Maddocks ◽  
...  
Keyword(s):  
Phase I ◽  
B Cell ◽  
Disease Progression ◽  
Dose Level ◽  
Dose Escalation ◽  
Research Funding ◽  
Phase I Study ◽  
Hematologic Toxicity ◽  
Off Label ◽  
Grade 3

Abstract Introduction: Lenalidomide, an immunomodulatory agent, and ibrutinib, a selective and covalent inhibitor of Bruton's tyrosine kinase, are orally bioavailable agents with single-agent activity in several histologic subtypes of relapsed/refractory B-cell non-Hodgkin lymphoma (NHL). We are conducting a phase I study of the combination of ibrutinib and lenalidomide to determine the maximum tolerated dose, dose limiting toxicities (DLT), and preliminary efficacy in pts with relapsed/refractory NHL and updated results are presented. Methods: Patients (pts) with relapsed/refractory B-cell NHL including diffuse large B-cell (DLBCL), transformed, mantle cell (MCL), marginal zone (MZL), lymphoplasmacytic (LPL), and follicular (FL) lymphoma who have received at least one prior therapy were eligible. Prior autologous but not allogeneic stem cell transplant and prior lenalidomide were permitted. Prior ibrutinib, CNS involvement, and pts requiring anticoagulation were not permitted. ANC > 1000/mm3, platelets > 50,000/mm3, and creatinine < 2.0 mg/dL, ALT/AST ≤ 2.5 x ULN, bilirubin ≤ 1.5 x ULN, and ECOG PS 0-2 were required at study entry. Treatment consisted of escalating doses of lenalidomide days 1-21 and ibrutinib days 1-28 of a 28 day cycle. A standard 3+3 dose escalation schema was followed. DLTs included: treatment delays > 14 days for toxicity; grade 5 toxicity; tumor lysis syndrome requiring dialysis; tumor flare reaction nonresponsive to corticosteroids; ANC < 500/mm3 or platelets <25, 000/mm3 persisting > 7 days; grade 3 or 4 febrile neutropenia or infection; and any grade 3 or 4 non-hematologic toxicity with the following exceptions: DVT, diarrhea, nausea or vomiting amenable to medical therapy, correctable electrolyte abnormalities; grade 3 fatigue, or grade 3 maculopapular rash that resolved within 7 days. Pts without significant toxicity could continue treatment until disease progression. Response was assessed every 3 months for 12 months and then every 6 months until disease progression. Results: Twenty-five pts have been treated. Median age is 67 years (range 45-85) with 16 males. Histologies include DLBCL/transformed lymphoma (n=9), MCL (n=7), FL (n=4), MZL (n=2), and LPL (n=3). Four pts were treated at dose level (DL) 1 (lenalidomide 15 mg/ibrutinib 420 mg). One pt was replaced for rapid disease progression and 1 pt experienced DLT consisting of a grade 2 ischemic stroke. As a result of this DLT, DL 1 was expanded to 6 evaluable pts. A second DLT was observed, a grade 3 rash that resolved within 7 days but recurred on day 22. A total of 6 pts were then treated at DL-1 (lenalidomide 10 mg/ibrutinib 280 mg), and no DLTs were encountered. The protocol was amended to include additional dose levels. Pts enrolled on dose level -1A with lenalidomide 10 mg and ibrutinib 420 mg. One DLT occurred at this dose level, a grade 3 rash that failed to resolve within 7 days. The dose level was expanded to 6 pts without further DLT. DL-1B includes an intra-pt dose escalation of the lenalidomide from 10 mg in cycle 1 to 15 mg in cycle 2 with ibrutinib 420 mg. Six pts have been enrolled on this dose level. Three pts have been replaced including 2 with cytopenias not meeting DLT criteria but precluding dose escalation and one with progressive disease. Three pts at DL-1B remain on treatment. Related grade 3-4 toxicities occurred in 16/24 currently evaluated pts (67%), including primarily hematologic toxicity, rash, increased LFTs, pneumonia, hypokalemia, and syncope. Pts have received a median of 3 cycles of therapy to date (range 1-19) and 9 remain on therapy. At DL 1, a pt with DLBCL achieved a complete response (CR) and a pt with transformed follicular achieved a partial response (PR). At DL-1, a pt with DLBCL achieved a CR and 1 pt each with MCL and FL achieved PR. At DL -1A, 1 pt each with MCL and MZL achieved a PR. Overall response rate for 18 assessable pts is 39%. Five pts had best response of stable disease. Sixteen pts have discontinued the study including 3 pts with DLTs, 2 for alternative treatment, 2 for toxicity, and 9 pts with progression. Conclusions: Combined therapy with lenalidomide and ibrutinib in pts with relapsed NHL is well-tolerated, although DLTs of recurrent rash and stroke were encountered. Lenalidomide 10 mg and ibrutinib 420 mg was tolerated and pts are currently enrolling in an intra-pt dose escalation cohort. Preliminary efficacy has been observed in pts with relapsed/refractory DLBCL, MCL, FL, MZL, and transformed NHL. Disclosures Christian: Pharmacyclics: Research Funding; Acerta: Research Funding; Immunomedics: Research Funding; Celgene: Consultancy; Novartis: Other: IDSM; Seattle Genetics: Consultancy, Research Funding; Janssen: Research Funding. Off Label Use: The use of ibrutnib and lenalidomide in combination in relapsed/refractory non-Hodgkin's lymphoma is off-label. Kuruvilla:Karyopharm: Honoraria, Research Funding; Roche Canada: Honoraria; Seattle Genetics: Honoraria, Research Funding. Smith:Celgene: Consultancy; Pharmacyclics: Consultancy. Porcu:Cell Medica: Research Funding; Infinity: Research Funding; Seattle Genetics: Research Funding; Celgene: Research Funding; Shape: Research Funding. Maddocks:Acerta: Research Funding; Pharamcyclics: Research Funding; Novartis: Research Funding. Byrd:Pharmacyclics: Research Funding. Blum:Celgene: Research Funding; cephalon: Research Funding; Pharmacyclics: Research Funding; Janssen: Research Funding.

scholarly journals A Phase I Study of Ibrutinib and Lenalidomide in Patients with Relapsed and Refractory B-Cell Non-Hodgkin's Lymphoma

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4476-4476 ◽  
Author(s):  
Beth Christian ◽  
John Kuruvilla ◽  
Sonali Smith ◽  
Pierluigi Porcu ◽  
Amy S. Ruppert ◽  
...  
Keyword(s):  
Phase I ◽  
B Cell ◽  
Disease Progression ◽  
Dose Level ◽  
Dose Escalation ◽  
Stable Disease ◽  
Research Funding ◽  
Phase I Study ◽  
Mantle Cell ◽  
Grade 3

Abstract Introduction: Lenalidomide, an immunomodulatory agent, and ibrutinib, a selective and covalent inhibitor of Bruton’s tyrosine kinase, are orally bioavailable agents with promising single agent activity in relapsed/refractory B-cell NHL. We are conducting a phase I study of the combination of ibrutinib and lenalidomide to determine the maximum tolerated dose, dose limiting toxicities (DLT), and preliminary efficacy in patients with relapsed/refractory NHL. Methods: Patients with relapsed/refractory B-cell NHL including diffuse large B-cell (DLBCL), transformed, mantle cell, marginal zone, lymphoplasmacytic, and follicular lymphoma who have received at least one prior therapy were eligible. Prior autologous but not allogeneic stem cell transplant and prior lenalidomide were permitted. Prior ibrutinib, CNS involvement, and patients requiring anticoagulation were not permitted. ANC > 1000/mm3, platelets > 50,000/mm3, and creatinine < 2.0 mg/dL, ALT/AST ≤ 2.5 x ULN, bilirubin ≤ 1.5 x ULN, and ECOG PS 0-2 were required at study entry. Treatment consisted of escalating doses of lenalidomide days 1-21 and ibrutinib days 1-28 of a 28 day cycle. A standard 3+3 dose escalation schema was followed. DLTs were assessed during cycle 1 and included: treatment delays > 14 days for toxicity; grade 5 toxicity; tumor lysis syndrome requiring dialysis; tumor flare reaction nonresponsive to corticosteroids; ANC < 500 / mm3 or platelets <25, 000 / mm3 persisting > 7 days; grade 3 or 4 febrile neutropenia or infection; and any grade 3 or 4 non-hematologic toxicity with the exception of DVT, diarrhea, nausea, or vomiting amenable to medical therapy, correctable electrolyte abnormalities; grade 3 fatigue, or grade 3 maculopapular rash that resolved within 7 days. Patients without significant toxicity could continue treatment until disease progression. Response was assessed every 3 months for 12 months and then every 6 months until disease progression. Results: From September 2013 until July 2014, 13 patients have been treated. Median age is 68 years (range 45-85) with 9 males. Histologies include DLBCL (4), transformed (4), follicular (2), mantle cell (2), and lymphoplasmacyctic (1) lymphoma. Median number of prior therapies is 3 (range 2-9) with 4 patients having undergone prior autologous transplant. Four patients were treated at dose level (DL) 1 (lenalidomide 15 mg and ibrutinib 420 mg). One patient was replaced for rapid disease progression and 1 patient experienced DLT consisting of a grade 2 ischemic stroke while on aspirin with no history of cardiovascular disease that resulted in discontinuation of study therapy. As a result of this DLT, dose level 1 was expanded to 6 patients. A second DLT was observed, a grade 3 rash that resolved within 7 days with interruption of therapy but recurred with diffuse erythroderma within 4 hours of ibrutinib resumption on day 22 at 280 mg. A total of 6 patients were then treated at DL -1 (lenalidomide 10 mg and ibrutinib 280 mg), and no DLTs were encountered. Related grade 3-4 toxicities occurred in 4/13 patients (31%), including one patient with hypokalemia, neutropenia, thrombocytopenia, and pneumonia, two others with neutropenia and one with maculapapular rash. Patients have received a median of 3 cycles of therapy to date (range 1-5) and 5 remain on therapy. At DL 1, a patient with DLBCL achieved a complete response (CR) and patient with transformed follicular achieved a partial response (PR). At DL -1, a patient with DLBCL achieved a CR and a patient with mantle cell lymphoma achieved a PR. Four patients achieved stable disease. Reasons for study discontinuation include two patients with DLTs who were not evaluated for response, one patient with stable disease who went off study for alternative treatment, and five patients who have progressed. Conclusions: Combined therapy with lenalidomide and ibrutinib in patients with relapsed NHL has been well tolerated at doses of 10 mg and 280 mg respectively, although DLTs of recurrent rash and stroke were encountered with 15 mg lenalidomide and 420 mg ibrutinib. Dose escalation to an intermediate dose level with lenalidomide 10 mg and ibrutinib 420 mg is planned. If this dose level is deemed safe, intra-patient dose escalation of the lenalidomide from 10 mg in cycle 1 to 15 mg in cycle 2 with ibrutinib 420 mg continuously will be tested. Preliminary efficacy has been observed in patients with relapsed/refractory DLCL, MCL, and transformed NHL. Disclosures Christian: Janssen Research & Development, LLC: Research Funding; Celgene: Consultancy. Off Label Use: Use of lenalidomide and ibrutinib in B-cell non-Hodgkin's lymphoma. Smith:Celgene: Consultancy, Research Funding; Pharmacyclics/Janssen: Consultancy, Speakers Bureau. Porcu:Celgene: Honoraria. Byrd:Phamacyclics: Research Funding. Blum:Janssen, Pharmacyclics: Research Funding.

scholarly journals The Novel PI3K/mTOR Dual Inhibitor PQR309 in Pre-Clinical Lymphoma Models: Demonstration of Anti-Tumor Activity As Single Agent and in Combination and Identification of Gene Expression Signatures Associated with Response

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1782-1782
Author(s):  
Chiara Tarantelli ◽  
Eugenio Gaudio ◽  
Ivo Kwee ◽  
Andrea Rinaldi ◽  
Matteo Stifanelli ◽  
...  
Keyword(s):  
Gene Expression ◽  
Phase I ◽  
B Cell ◽  
Cell Lines ◽  
Proliferative Activity ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Single Agent ◽  
B Cell Lymphoma ◽  
Dual Inhibitor

Abstract Dual PI3K/mTOR inhibitors represent a promising class of anti/cancer compounds, of potential interest in lymphoid neoplasms which present activation of both targeted pathways. PQR309 is a novel, oral, member of this class of compounds and, as single agent, is currently being evaluated in a phase I for patients with solid tumors (NCT01940133). Here, we present the activity of the compound in pre-clinical models of mature lymphoid tumors, also integrating response data with genomic features. Methods. 48 cell lines [27 derived from diffuse large B-cell lymphoma (DLBCL), 10 from mantle cell lymphoma (MCL), 3 from splenic marginal zone lymphoma (SMZL), 8 from anaplastic large cell lymphoma (ALCL)] were treated with increasing doses of PQR309 and MTT assays were performed after 72 hrs exposure. A second dual PI3K/mTOR inhibitor, GDC0980, and the PI3Kdelta inhibitor Idelalisib were also used on all the cell lines. IC50, GI50, LC50, and TGI values were used to estimate the cytotoxic and cytostatic effects. PQR309-induced cytotoxic activity was tested by AnnexinV assay. Synergy was assessed by the Chou-Talalay combination index (CI) on 2 DLBCL cell lines (TMD8, U2932) exposed to increasing doses of PQR309 alone or in combination with increasing doses of other drugs for 72 hrs. Baseline gene expression profiling (GEP) was obtained on the cell lines with the Illumina HumanHT-12 Expression BeadChips and integrated with the anti-proliferative effect. Results. PQR309 showed potent anti-proliferative activity in most of the cell lines tested. The median IC50 was 242 nM (18nM-3.6 mcM), GI50 141 nM (25 nM-1.7 mcM), LC50 2.7 mcM (306 nM->10 mcM), TGI 711 nM (69 nM - >10 mcM). DLBCL (median IC50=166 nM), MCL (234 nM) and SMZL (214 nM) were all more sensitive than ALCL (664 nM) (P=0.005). Activated B-cell like (ABC) and germinal center B-cell like (GCB) DLBCL subtypes were equally sensitive. Across the 48 cell lines, PQR309 and GDC0980 presented a highly correlated pattern of anti-proliferative activity (R=0.95). Idelalisib appeared significantly less active and its pattern of sensitive cell lines was less correlated with PQR309 (R=0.67) or GDC0980 (R=0.71). In DLBCL cell lines, PQR309 (1 mcM) was able to inhibit IgM-stimulation induced p-AKT(Ser 473) in 2/2 cells and the baseline p-AKT(Ser 473) levels in 1/1. PQR309 (500 nM, 72 hrs) caused apoptosis in 1/7 cell lines. Synergism or additive effected were observed in 2/2 cells combining PQR309 with the BCL2 inhibitor ABT199 (CI = 0.1 and 0.5), the immunomodulatory drug lenalidomide (0.5 and 0.4), the BTK-inhibitor ibrutinib (0.6 and 0.57) or the proteasome inhibitor bortezomib (0.9 and 0.9), and in 1/2 with the anti-CD20 monoclonal antibody rituximab (0.6), the BET inhibitor JQ1 (0.7) and the chemotherapy agent bendamustine (0.7). We then looked for baseline GEP features associated with sensitivity to PQR309, by comparing very sensitive (IC50 < 200 nM) versus less sensitive DLBCL cell lines (IC50 > 400 nM). Transcripts more expressed in sensitive cells were significantly enriched of genes involved in B-cell receptor pathway/signaling, kinases regulation, immune system. Transcripts associated with less sensitive cells were enriched of members of proteasome pathway, oxidative phosphorylation, translation initiation. Genes coding for individual proteins involved in PI3K signaling cascade were differentially expressed between the two groups of cells. Conclusions. PQR309 showed promising activity as single agent and in combination providing the basis for phase I/II studied dedicated for lymphoma patients. Baseline features associated with response were identified and are worth of being validated in the context of the next clinical trials. (CT and EG contributed equally to this work) Disclosures Hillmann: Piqur Therapeutics AG: Employment. Fabbro:Piqur Therapeutics AG: Employment. Hebeisen:Piqur Therapeutics AG: Employment. Betts:Piqur Therapeutics AG: Consultancy. Wicki:Piqur Therapeutics AG: Research Funding; University Hospital Basel: Employment. Cmiljanovic:Piqur Therapeutics AG: Employment, Membership on an entity's Board of Directors or advisory committees. Bertoni:Piqur Therapeutics AG: Research Funding.

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