A Dose Escalation Study of RP6530, a Novel Dual PI3K Delta/Gamma Inhibitor, in Patients with Relapsed/Refractory Hematologic Malignancies

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1495-1495 ◽  
Author(s):  
Carmelo Carlo-Stella ◽  
Richard Delarue ◽  
Prajak J Barde ◽  
Lydia Scarfo ◽  
Thamila Saheb ◽  
...  
Keyword(s):  
Disease Progression ◽  
Dose Escalation ◽  
Research Funding ◽  
Performance Status ◽  
Single Agent ◽  
Plasma Concentrations ◽  
Hematologic Malignancies ◽  
Prognostic Scores ◽  
Dose Escalation Study ◽  
Human Dose

Abstract Introduction: Phosphoinositide-3-kinases (PI3Ks) are pivotal in cell proliferation and survival, cell differentiation, intracellular trafficking and immunity. The delta (δ) and gamma (γ) isoforms of PI3K are often dysregulated in various hematologic malignancies and therefore key targets for the treatment of lymphomas/ leukemia. RP6530 is a novel, highly specific dual PI3K δ/γ inhibitor with nanomolar inhibitory potency that effectively inhibits AKT phosphorylation and induces apoptosis in lymphoma/leukemic cell lines. We herein present results from an ongoing Phase I, first-in-human, dose escalation study of RP6530 (NCT02017613). Methods: The dose escalation will determine the maximum tolerated dose (MTD) of RP6530 using a standard 3+3 design. Patients (pts) with a confirmed diagnosis of hematological malignancy and at least one prior therapy are eligible. Additional eligibility criteria include an ECOG performance status ≤ 2, measurable/evaluable disease, and life expectancy of at least 12 weeks. Primary endpoints are safety and pharmacokinetic (PK) and are supported by secondary endpoints such as pharmacodynamic and efficacy parameters (overall and complete response rates) and correlative biomarkers. RP6530 is given orally twice daily in 28-day cycles until disease progression, unacceptable toxicity, or withdrawal from study. The study is designed to enroll up to 120 pts in the dose-escalation and expansion phase. Adverse events (AE) are assessed using the CTCAE v4.0/IWCLL guidelines as applicable. Efficacy evaluations are conducted every 8 wks. Results: Twenty six pts were enrolled to date across various dose levels: BID 25mg, 50mg, 100mg, 200mg, 400mg, 600mg and 800mg. Sixteen were males; ECOG score was 0/1/2 in 20/3/3 pts, respectively, with a mean age of 59 yrs (range 20-83). Pts had a median of 5 (range: 1-11) prior treatment regimens, and 19 were refractory to prior treatments. Malignancy categories included HL (9), TCL (4), DLBCL (4), MCL (3), CLL/SLL (2), FL (1), MZL (1), WM (1), and MM (1). Majority of them were considered as "high tumor burden patients" as per different prognostic scores. Sixteen patients were discontinued mainly due to disease progression. RP6530 was well tolerated with no DLT reported to date. Majority of AEs were mild and resolved with/without concomitant medication. None of Grade III/IV AEs or SAEs were deemed related to RP6530. No drug related increase in ALT/AST, colitis, pneumonia, or neutropenia was observed to date. Dose escalation is currently ongoing at 800 mg BID. Single agent activity, manifested by a reduction in tumor size by CT or PET scan, was noticed at ≥ 200 mg BID. The efficacy observations are mostly in indications, that are difficult-to-treat or with minimal therapeutic options. The ORR is 20 % [CR 2 (10 %) + PR 2 (10%)] with disease control rate of 65%. The responders are HL (2), PTCL (1) and DLBCL (1). The CLL/SLL patients, known to be the best responders to selective PI3K inhibitors, were not included in dose-cohorts ≥ 200 mg BID. Clinical response was associated with a significant reduction in pAKT expression. Dose-proportional increase in plasma concentrations were observed upon oral administration of RP6530. Conclusions: To date, RP6530 has been well tolerated in pts with heavily pre-treated relapsed/refractory hematologic malignancies. Reported toxicities were manageable with no DLTs. Single agent activity was evident in difficult-to-treat patients at ≥ 200 mg BID. Enrolment continues at higher dose cohorts. Updated safety, efficacy, PK, and PD data will be presented at the annual meeting. Disclosures Barde: Rhizen Pharmaceuticals SA: Employment. Kumar:Rhizen Pharmaceuticals SA: Employment. Viswanadha:Incozen: Employment. Vakkalanka:Rhizen Pharmaceuticals SA: Employment, Equity Ownership. Ghia:Adaptive: Consultancy; GSK: Research Funding; Acerta Pharma BV: Research Funding; Roche: Consultancy, Research Funding; Pharmacyclics: Consultancy; AbbVie: Consultancy; Janssen: Consultancy; Gilead: Consultancy, Research Funding, Speakers Bureau.

Dose-escalation study of SAR439859, an oral selective estrogen receptor (ER) degrader (SERD), in postmenopausal women with ER+/HER2- metastatic breast cancer (mBC).

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 1054-1054
Author(s):  
Aditya Bardia ◽  
Hannah M. Linden ◽  
Gary A. Ulaner ◽  
Sarat Chandarlapaty ◽  
Alice Gosselin ◽  
...  
Keyword(s):  
Postmenopausal Women ◽  
Endocrine Therapy ◽  
Dose Escalation ◽  
Phase 1 ◽  
Performance Status ◽  
Dose Range ◽  
Single Agent ◽  
Plasma Concentrations ◽  
Metastatic Breast ◽  
Dose Escalation Study

1054 Background: SERDs result in ER competitive antagonism and degradation and can block signaling in ER-dependent tumors resistant to other endocrine therapies. This study investigates SAR439859, a potent oral SERD, +/- palbociclib in ER+/HER2- mBC. Here are preliminary results, as of 28 Nov 2018, for single-agent SAR439859 dose escalation. Methods: Part A of this Phase 1/2 study (NCT03284957; TED14856) assessed SAR439859 dose escalation (dose range: 20–600 mg once daily [QD]; 3 + 3 design) in postmenopausal women with ER+/HER2- mBC treated for ≥ 6 months with prior endocrine therapy and ≤ 3 chemotherapies in the advanced setting. Endpoints: dose-limiting toxicities (DLTs); maximum tolerated dose (MTD); safety; pharmacokinetics (PK); tumor response (RECIST 1.1); pharmacodynamic (PD) inhibition of ER occupancy (18FES-PET scan). Results: Patients (pts; n = 16) had a median age of 59.5 years (range 40–79), ECOG performance status of 0 (62.5%) or 1 (37.5%) and a median of three prior anticancer therapies (range 1–8) in the advanced setting (endocrine therapy n = 16; chemo/targeted therapy n = 13). All pts had ≥ 1 treatment emergent adverse event (mostly grade 1–2); most frequent were asthenia/fatigue (43.8%), hot flushes (37.5%), nausea (37.5%), diarrhea (31.3%), constipation (31.3%), and decreased appetite (31.3%). There were no DLTs at any of the five dose levels (maximum administered dose: 600 mg QD); MTD was not reached. In 18FES-PET scans, signal inhibition > 87% occurred with plasma concentrations > 100 ng/mL. There was a dose proportional increase of exposure up to 400 mg after repeated QD doses. Average Ctrough was reached after repeated 400 mg QD allowing 90% of 18FES-PET signal inhibition. One pt (6.3%) had confirmed partial response (150 mg QD); eight (50%) had stable disease (SD) including three (18.8%) long-term SD (≥ 24 weeks); seven (43.8%) had progressive disease. Conclusions: SAR439859 had a favorable safety profile, high ER occupancy and encouraging antitumor activity (to be confirmed in dose expansion) in pretreated pts with ER+/HER2- mBC. With no DLTs and MTD, 400 mg QD was selected for expansion cohorts based on safety, PD and PK data. Funding: Sanofi. Clinical trial information: NCT03284957.

A Phase I Dose Escalation Study of RP6530, a Novel, Dual PI3K-γδ Inhibitor, for Patients with Relapsed or Refractory Hematologic Malignancies

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3043-3043 ◽  
Author(s):  
Lydia Scarfò ◽  
Prajak J Barde ◽  
Claudia Fazi ◽  
Uday Kumar ◽  
Srikant Viswanadha ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Phase I ◽  
Disease Progression ◽  
Dose Escalation ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Lymphoblastic Leukemia ◽  
Performance Status ◽  
Hematologic Malignancies ◽  
Lymphocytic Leukemia

Abstract Introduction: Phosphoinositide-3-kinases (PI3Ks) are pivotal in various cellular functions including cell proliferation and survival, cell differentiation, intracellular trafficking and immunity. The delta (δ) and gamma (γ) isoforms of PI3K are highly expressed in cells of hematopoietic origin, and often dysregulated in various hematologic malignancies. Because these isoforms contribute to the development, maintenance, transformation, and proliferation of immune cells, dual targeting of PI3K δ and γ represents a promising approach in the treatment of lymphomas. RP6530 is a novel, highly specific dual PI3K δ/γ inhibitor with nanomolar inhibitory potency at the enzyme and cellular level. Besides, RP6530 was effective in inhibiting Akt phosphorylation and inducing apoptosis in various lymphoma and leukemic cell lines. Herein we present preliminary results of a Phase I, first in human, open label study of an oral PI3K δ/ γ inhibitor, RP6530. (NCT02017613). Methods: The dose escalation will determine the maximum tolerated dose (MTD) of RP6530 using a standard 3+3 design. Patients (pts) with a confirmed diagnosis of B-cell non-Hodgkin lymphoma, peripheral T-cell lymphoma, chronic lymphocytic leukemia, Acute lymphoblastic leukemia (CLL), Primary central nervous system lymphomas or Multiple myeloma who have at least one prior therapy are eligible. Additional eligibility criteria include ECOG performance status ≤ 2, and measurable/evaluable disease with a life expectancy of at least 12 weeks. Primary endpoints are safety and pharmacokinetic (PK) parameters; secondary endpoints include pharmacodynamic and drug activity (overall and complete response rates). Correlative biomarker samples including quantitative/qualitative measurements of cytokines, chemokines and aberrations indicative of PI3K function and RP6530 efficacy will be analyzed. RP6530 is given orally twice daily in 28-day cycles until disease progression, unacceptable toxicity, or withdrawal from treatment. The study is designed to enroll up to 30 pts in the dose-escalation phase with up to an additional 42 pts in the cohort expansion phase. Efficacy evaluations are planned every 8 weeks. Adverse events (AE) are assessed using the CTCAE v4.0/ IWCLL guidelines as applicable. Results: Nine pts were enrolled to date across 3 dose levels: BID 25mg, 50mg and 100mg. Five pts were males; ECOG score was 0/1/2 in 5/1/3 pts, respectively, with mean age of 74 yrs (range: 54-82). Pts had median 5 (range: 1-11) prior treatment regimens, and 6 were refractory to prior treatments. Lymphoma categories included DLBCL (2 pts), Mantle Cell Lymphoma (2 pts), follicular lymphoma (1 pt), Marginal Zone Lymphoma (1 pt); and CLL/SLL (2 pts); one pt had multiple myeloma. All nine pts are evaluable for DLT assessment. Of the 9 evaluable pts, 6 are currently on study; 1 patient discontinued treatment due to disease progression. Pts tolerated the treatment well. To date, there have been no DLTs. One pt experienced G4 neutropenia that was unrelated to RP6530. No other G3/4 related hematologic or non-hematologic toxicities were observed. Of the six pts who completed 2 cycles of treatment (8 wks) at 50 mg daily dosing or less, 5 showed stable disease while 1 had disease progression. Three pts did not reach the first response assessment. Mean PK parameters determined on Day 1 of Cycle 1(C1D1) are: median Tmax of 1 hrs (range 0.5-2.0hrs), harmonic mean t1/2 of 2 (± 0.47) hr, and CL/F of 39.55 (± 19.3) L/hr. A linear relationship exists between dose and both AUC (r2 = 0.97) and Cmax (r2 = 0.97). The average accumulation index represented by Cmin on Cycle 2 day 1 is 1.12 (± 0.1). PK data from the first 3 cohorts on C1D1 is summarized below. Table 1.Dose25 mg (n=3)50 mg (n=3)100 mg (n=3)Cmax (µg/mL)0.356 (± 0.08)0.563 (± 0.12)1.329 (± 0.55)AUC (µg*hr/mL)0.775 (± 0.32)1.619 (± 0.67)2.482 (± 1.18) Conclusions: To date, RP6530 has been well tolerated in pts with heavily pre-treated relapsed/refractory hematologic malignancies. There were no DLTs and toxicities were minimal. Enrollment continues at higher dose cohorts. Updated safety, efficacy, PK, and PD data will be presented. Disclosures Scarfò: Rhizen Pharmaceuticals SA: Research Funding. Barde:Rhizen Pharmaceutical SA: Employment. Fazi:Rhizen Pharmaceuticals SA: Research Funding. Kumar:Rhizen Pharmaceuticals SA: Employment. Viswanadha:Incozen: Employment. Vakkalanka:Rhizen Pharmaceuticals SA: Employment, Equity Ownership. Ghia:Rhizen Pharmaceuticals SA: Research Funding. Ferreri:Rhizen Pharmaceuticals SA: Research Funding.

Venetoclax Combined with Bortezomib and Dexamethasone for Patients with Relapsed/Refractory Multiple Myeloma

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 975-975 ◽  
Author(s):  
Philippe Moreau ◽  
Asher A. Chanan-Khan ◽  
Andrew W. Roberts ◽  
Amit B. Agarwal ◽  
Thierry Facon ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Respiratory Failure ◽  
Disease Progression ◽  
Cardiac Failure ◽  
Dose Escalation ◽  
Research Funding ◽  
Objective Response ◽  
Lower Abdominal Pain ◽  
Cell Transplant ◽  
Dose Escalation Study

Abstract Background: BCL-2 and MCL-1 promote multiple myeloma (MM) cell survival. Venetoclax (VEN) is a potent, selective, orally bioavailable small-molecular inhibitor of BCL-2. When combined with bortezomib, which can inhibit MCL-1, VEN can enhance the activity of bortezomib in MM cell lines and xenograft models. Methods: In this Phase 1b, open label, dose escalation study, patients with relapsed/refractory (R/R) MM received daily VEN (50 - 1200 mg per designated dose cohort) with bortezomib and dexamethasone. The objectives of the study were to assess the safety, pharmacokinetics, maximum tolerated dose, recommended phase 2 dose (R2PD), and efficacy (objective response rate [ORR], time to progression [TTP], and duration of response [DoR]) of combination therapy in this patient population. Results: As of 01July2016, 66 patients were enrolled, with 54 in the dose escalation cohort and 12 in the safety expansion at R2PD of 800 mg. The median age was 64 years and 39 (59%) were ISS stage II/III. The median number of prior therapies was 3 (range: 1 - 13), and 21 (32%) were refractory to prior bortezomib, 37 (56%) were refractory to prior lenalidomide, and 41 (62%) had prior stem cell transplant. Forty-three (65%) patients discontinued the study for the following primary reasons: 33 related to disease progression, 5 due to AEs (1 each: respiratory failure and cardiac failure, lung adenocarcinoma, sepsis, renal impairment, and Guillain-Barre syndrome; none were considered by the investigator as related to VEN), 2 withdrew consent, and 3 for other reasons not specified. Adverse events (AEs) were reported in 65 (99%) patients, with common AEs in ≥20% of patients being diarrhea (41%), thrombocytopenia (39%), constipation (38%), nausea (36%), insomnia (32%), peripheral neuropathy (30%), peripheral edema (29%), anemia (27%), peripheral sensory neuropathy (27%), dyspnea (24%), fatigue (24%), and asthenia (24%). Grade 3/4 AEs in ≥10% of patients included thrombocytopenia (29%), anemia (15%) and neutropenia (14%). Serious AEs in ≥2 patients were febrile neutropenia, thrombocytopenia, cardiac failure, pyrexia, influenza, lower respiratory tract infection, pneumonia, sepsis, acute kidney injury, respiratory failure, embolism, and hypotension. One dose-limiting toxicity of lower abdominal pain was reported for a patient who received 1200 mg VEN. Five deaths were reported during the study, 4 due to disease progression and 1 due to respiratory syncytial virus infection (not considered by the investigator as related to VEN). After co-administration with bortezomib and dexamethasone, dose-normalized VEN exposure at steady-state appeared to be within the exposure range observed with VEN monotherapy in patients with MM. The ORR for all evaluable patients was 68% (44/65) and 26 (40%) achieved very good partial response (VGPR) or better (3 stringent complete response [sCR], 8 CR, 15 VGPR) (Figure). For all patients, median DoR was 8.8 months (95% CI: 7.2, 15.8) and TTP was 8.6 months (95% CI: 5.7, 10.2), with a median follow up of 4.9 months (range: .03 - 26.7). High ORR of 89% was seen in patients who were non-refractory to prior bortezomib (39/45) or who had 1 - 3 prior therapies (31/35). In 31 patients who were non-refractory to bortezomib and had 1 - 3 prior therapies had ORR of 94% (29/31), 68% (21/31) with VGPR or better; median DoR was 10.6 months and TTP was 11.3 months for this subgroup. Moreover, patients who were bortezomib naïve and had 1 - 3 prior lines of therapy had ORR of 100% (12/12), and median DoR was 15.8 months and TTP was 17.1 months. In patients who were non-refractory to prior bortezomib but who were refractory to lenalidomide, the ORR was 86% (19/22) as compared with 91% (20/22) in those non-refractory to lenalidomide. Clinical responses were comparable in patients with t(11;14) MM (ORR, 78% [7/9]) and without t(11;14) MM (ORR, 66% [37/56]). In the t(11;14) group, 3 patients were bortezomib-refractory, and 2 of them achieved a PR as best response. Also, 4 patients had more than 3 prior lines, with 3 of them achieving PR. Conclusions: VEN in combination with bortezomib and dexamethasone has an acceptable safety profile in patients with R/R MM. Efficacy results, including 68% ORR in all patients and 94% ORR in patients not refractory to bortezomib and who received 1 - 3 prior lines of therapy, indicates promising efficacy of this novel combination and supports the ongoing Phase 3 trial with this regimen in patients with R/R MM. Figure. Figure. Disclosures Moreau: Janssen: Honoraria, Speakers Bureau; Novartis: Honoraria; Takeda: Honoraria; Celgene: Honoraria; Amgen: Honoraria; Bristol-Myers Squibb: Honoraria. Roberts:Genentech: Patents & Royalties: Employee of Walter and Eliza Hall Institute of Medical Research which receives milestone payments related to venetoclax; AbbVie: Research Funding; Servier: Research Funding; Janssen: Research Funding; Genentech: Research Funding. Agarwal:AbbVie: Honoraria, Research Funding; Millennium: Consultancy; Amgen: Consultancy; Janssen: Speakers Bureau; Onyx: Speakers Bureau; Celgene: Speakers Bureau. Facon:Amgen: Consultancy, Speakers Bureau; Millenium/Takeda: Consultancy; Bristol: Consultancy; Janssen: Consultancy, Speakers Bureau; Novartis: Consultancy; Celgene: Consultancy, Speakers Bureau; Karyopharm: Consultancy. Kumar:Glycomimetics: Consultancy; AbbVie: Research Funding; Janssen: Consultancy, Research Funding; Onyx: Consultancy, Research Funding; BMS: Consultancy; Celgene: Consultancy, Research Funding; Array BioPharma: Consultancy, Research Funding; Millennium: Consultancy, Research Funding; Sanofi: Consultancy, Research Funding; Kesios: Consultancy; Skyline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Noxxon Pharma: Consultancy, Research Funding. Touzeau:AbbVie: Research Funding. Cordero:AbbVie: Employment. Ross:AbbVie: Employment, Equity Ownership. Munasinghe:AbbVie: Employment. Jia:AbbVie: Employment. Salem:AbbVie: Employment. Leverson:AbbVie: Employment, Other: Shareholder in AbbVie. Maciag:AbbVie: Employment. Verdugo:AbbVie: Employment, Other: may own stock. Harrison:Janssen Cilag: Research Funding, Speakers Bureau; AbbVie: Research Funding.

scholarly journals Combination Trial of Duvelisib (IPI-145) with Bendamustine, Rituximab, or Bendamustine/Rituximab in Patients with Lymphoma or Chronic Lymphocytic Leukemia

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3928-3928 ◽  
Author(s):  
Ian W. Flinn ◽  
Mohamad Cherry ◽  
Michael Maris ◽  
Jeffrey V. Matous ◽  
Jesus G. Berdeja ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Disease Progression ◽  
Dose Level ◽  
Dose Escalation ◽  
Research Funding ◽  
Single Agent ◽  
Lymphocytic Leukemia ◽  
Expansion Phase ◽  
Time Plot

Abstract Background: Duvelisib, a potent inhibitor of the δ and γ isoforms of phosphoinositide-3-kinase (PI3K) is being developed as a potential therapeutic in hematologic malignancies including chronic lymphocytic leukemia (CLL), as well as B and T cell lymphoma. Single agent bendamustine (B), rituximab (R), and their combination have demonstrated proven activity in iNHL and CLL. Combining duvelisib with bendamustine or rituximab alone or with both drugs may improve response rates and the durability of remission. The primary objective of this trial is to characterize the safety, maximum tolerated dose (MTD), and a 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 with relapsed CLL or NHL, ECOG performance status (PS) ≤2, and adequate organ function were enrolled. 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 until disease progression or intolerance. Arm 2 (DBR)received rituximab 375 mg/m2 IV weekly for 2, 28 day cycles, bendamustine 90 mg/m2 IV for NHL pts or 70 mg/m2 IV for CLL pts on Days 1 and 2 of the first six cycles plus duvelisib PO BID until disease progression or intolerance. 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, 25, 50, and 75 mg PO BID were initially explored. Pts were evaluated for response every 3 cycles according to specific criteria for their disease. Results: Between August 2013 and April 2015, 48 pts, median age 67 yrs (40-83) were enrolled; 12 NHL pts in the dose escalation portion and 36 pts (18 CLL, 18 NHL) in dose expansion. Pts had a median of 2 prior therapies (1-7). 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), with a higher dose of bendamustine, 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). The MTD was not reached in this study but given recent data of single agent duvelisib showing no advantage in doses >25 mg BID, pts on the expansion phase were treated with 25mg BID. The AE profile of the drug combination is consistent with toxicities of the single agents (Table 1). There have been 2 potentially treatment-related deaths (cardiac arrest in a pt with history of hypertension and diabetes, and pneumonia), both on Arm 1. 38 pts were evaluable for response with an ORR of 74% (8% CR, 66% PR, 16% SD and 10% PD). The ORR of NHL and CLL pts were 64% and 92% respectively. With a median follow up of 16.25 mos, median progression free survival is 13.7 mos overall. Median overall survival (OS) has not been reached, but 15 mo OS probability is 82%. Pharmacokinetics analysis is consistent with the monotherapy Phase I trial of duvelisib (Figure 2) and is not effected by bendamustine. Conclusions: Analysis of duvelisib administered in combination with bendamustine and rituximab shows these combinations to be generally well-tolerated with encouraging response. Further follow-up is required to better characterize both response rates and durability of remissions. Table 1. Treatment-related AEs (≥15% all pts) ARM 1 (N=28) ARM 2 (N=18) ARM 3 (N=2) Preferred Term G 1/2 G 3/4 G 1/2 G 3/4 G 1/2 G 3/4 Treated (N=48) RASH 8 (29%) 3 (11%) 3 (17%) 3 (17%) 0 17 (35%) DIARRHEA 8 (29%) 3 (11%) 2 (11%) 1 (6%) 1 (50%) 0 15 (31%) FATIGUE 9 32%) 0 4 (22%) 1 (6%) 1 (50%) 0 15 (31%) NAUSEA 5 (18%) 0 4 (22%) 0 1 (50%) 0 10 (21%) ALANINE AMINOTRANSFERASE INCREASED 5 (18%) 1 (4%) 3 (17%) 0 0 0 9 (19%) NEUTROPENIA 1 (4%) 5 (18%) 0 3 (17%) 0 0 9 (19%) ASPARTATE AMINOTRANSFERASE INCREASED 4 (14%) 1 (4%) 3 (17%) 0 0 0 8 (17%) ANAEMIA 3 (11%) 1 (4%) 2 (11%) 0 1 (50%) 0 7 (15%) PRURITUS 3 (11%) 0 3 (17%) 0 0 0 6 (13%) UPPER RESPIRATORY TRACT INFECTION 5 (18%) 0 1 (6%) 0 0 0 6 (13%) CONSTIPATION 4 (14%) 0 1 (6%) 0 0 0 5 (10%) MUCOSAL INFLAMMATION 3 (11%) 1 (4%) 1 (6%) 0 0 0 5 (10%) Figure 1. Mean IPI-145 Concentration vs Time Plot with Tx Arms Overlaid for the First 6 Hours (Linear) Figure 1. Mean IPI-145 Concentration vs Time Plot with Tx Arms Overlaid for the First 6 Hours (Linear) Disclosures Flinn: Celgene Corporation: Research Funding. Berdeja:Curis: Research Funding; Abbvie: Research Funding; Janssen: Research Funding; Array: Research Funding; Acetylon: Research Funding; Takeda: Research Funding; Celgene: Research Funding; BMS: Research Funding; Onyx: Research Funding; MEI: Research Funding; Novartis: Research Funding.

First-in-human dose-escalation study of anti-EGFR ADC MRG003 in patients with relapsed/refractory solid tumors.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 3550-3550 ◽  
Author(s):  
Rui-hua Xu ◽  
Miao-Zhen Qiu ◽  
Yang Zhang ◽  
Xiao-Li Wei ◽  
Chaohong Hu
Keyword(s):  
Antitumor Activity ◽  
Adverse Events ◽  
Phase I ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Single Agent ◽  
Antibody Drug Conjugate ◽  
Dose Escalation Study ◽  
Egfr Expression ◽  
Human Dose

3550 Background: MRG003 is a novel antibody drug conjugate (ADC) composed of a fully human anti-EGFR IgG1 monoclonal antibody conjugated to a microtubule disrupting agent monomethyl auristatin E (MMAE). MRG003 is presently being tested in an ongoing phase I study for safety, pharmacokinetics, and preliminary antitumor activity in patients (pts) with solid tumors (CTR20180310). Methods: In the phase I dose escalation study of a traditional (3+3) design, pts with relapsed or refractory cancers received single agent MRG003 once every 3 weeks (Q3W) for a maximum of 8 treatment cycles. The starting dose of MRG003 is 0.1 mg/kg, followed by 0.3, 0.6, 1.0, 1.5, 2.0, 2.5, and 3.0 mg/kg. Observations included adverse events (AEs), dose-limiting toxicity (DLT), and antitumor activity which is assessed every two cycles. Results: A total of twenty-two pts with colorectal (CRC, n = 15), nasopharyngeal (NPC, n = 3), head and neck (H&N, n = 2), esophageal (EC, n = 1), and duodenal (DC, n = 1) cancer were enrolled in the dose escalation. The median age of pts was 56.5 years. The MTD identified was 2.5 mg/kg. Commonly observed adverse events were anemia (50%), AST increase (41%), decreased appetite (41%), rash (36%), pruritus (36%), asthenia (36%), and proteinuria (32%). Majority of AEs were mild to moderate in severity. EGFR expression in patients’ tumor samples was determined retrospectively by a validated IHC method in a central laboratory. Nine out of 22 pts tested were EGFR positive. Among these 9 EGFR positive pts, one with NPC in the 2.5 mg/kg cohort had partial response, four had stable disease (one with H&N in the 1.5 mg/kg, one each with NPC and H&N in the 2.0 mg/kg, and one with EC in the 2.5 mg/kg cohorts). The disease control rate (DCR) at doses ≥1.5 mg/kg was 100% for the EGFR positive pts. Conclusions: The dose escalation study of MRG003 showed manageable safety profiles and encouraging preliminary antitumor activity in pts with EGFR-positive solid tumors. MRG003 is currently being evaluated as a single agent in phase I dose expansion cohorts to further assess safety, PK, and antitumor activity. Clinical trial information: CTR20180310 .

A Phase I Study of Cloretazine® and Temozolomide in Patients with Hematologic Malignancies.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1971-1971 ◽  
Author(s):  
David A. Rizzieri ◽  
William Tse ◽  
Khuda D. Khan ◽  
Anjali Advani ◽  
Jon Donze ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Escalation ◽  
Single Agent ◽  
Pulmonary Hemorrhage ◽  
Hematologic Malignancies ◽  
Hematologic Toxicity ◽  
Dose Escalation Study ◽  
Futile Cycle ◽  
Grade 3 ◽  
Dna Strand

Abstract Background: In recent single agent Phase I trials, both Cloretazine® (VNP40101M) and temozolomide (TMZ) have shown activity in relapsed leukemia with minimal non-hematologic toxicity (Giles et al, 2004, Seiter et al, 2002). The cytotoxic activity of Cloretazine and TMZ have been attributed to the alkylation at the O6 position of guanine leading to a futile cycle of misincorporation of thymidine and ineffective mismatch repair. In addition, activation of Cloretazine generates different alkylating and isocyanate species that produce DNA cross linkages leading to DNA strand breaks and apoptosis. Repair of Cloretazine and TMZ induced alkylation lesions have been attributed to the expression and irreversible activity of enzyme O6 alkylguanine DNA alkyltranferase (AGT). It has been shown that TMZ administered to patients once or twice daily can reduce AGT levels in tumor cells; therefore depletion of AGT by TMZ may sensitize cells to Cloretazine and result in synergistic anti-tumor activity. Methods: Cloretazine given after TMZ priming is currently evaluated in a Phase I dose escalation study. Patients are eligible if they have relapsed or refractory leukemia (ECOG 0–2). TMZ was given orally starting at a dose of 200 mg twice daily for 5 doses. Cloretazine is given intravenously on day 3, 2–4 hours after the last dose of TMZ starting at 100 mg/m2. Dose escalation of TMZ was guided by AGT depletion in leukemic blasts assessed by enzyme assay and HPLC (Gerson et al, 1985). Leukemia response is assessed according for standard criteria for CR and CRp (Cheson et al, 2003). Results: Thirty-two patients have been treated in the first 5 cohorts (I: 200mg TMZ +100mg/m2 Cloretazine n=7, II: 300mg TMZ+100mg/m2 Cloretazine n=6, III: 300mg TMZ + 200mg/m2 Cloretazine n=3, IV: 300 mg TMZ + 300mg/m2 Cloretazine n=7, V: 300 mg TMZ + 400mg/m2 Cloretazine n=9). Median age of the patients is 62 years (range 27–80), M:F = 20:12. Treatment with 300mg TMZ x 5 doses resulted in >90% depletion of AGT levels in 5 of 6 patients in cohort II and was fixed for subsequent dose escalation with Cloretazine. Myelosuppression was the most frequent adverse event occurring in 10/32 (30%) of treated patients (6 Grade 3–4 neutropenia, 4 Grade 3–4 thrombocytopenia). Non-hematologic toxicity has been minimal. To date, two patients treated with TMZ 300mg x 5 and Cloretazine 400 mg/m2 have experienced dose-limiting toxicity: Grade 3 pulmonary hemorrhage and Grade 3 neutropenic colitis in Cohort V and no unexpected toxicities were observed. Three early deaths occurred within 30 days (9.4%), all attributed to progressive disease. Responses are as follows: CR=3, CRp=1, and HI=2 for an overall response rate of 18.8%. The study is ongoing. Conclusions: Cloretazine® in combination with TMZ is tolerable and manageable. Evidence of anti-tumor effect has already been observed suggesting the combination of Cloretazine® and TMZ may potentiate their antileukemic activity.

SAKK 65/08: A Phase I Dose Escalation Study of Bortezomib in Combination with Nelfinavir in Patients with Advanced Hematologic Malignancies

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4747-4747
Author(s):  
Christoph Driessen ◽  
Jürgen Bader ◽  
Marianne Kraus ◽  
Markus Jörger ◽  
Hilde Rosing ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Level ◽  
Dose Escalation ◽  
Plasma Concentrations ◽  
Hematologic Malignancies ◽  
Off Label Use ◽  
Dose Escalation Study ◽  
Off Label ◽  
Best Response

Abstract Rationale: Overcoming proteasome inhibitor (PI) resistance is a challenge in multiple myeloma (MM) therapy since most MM patients ultimately develop PI resistance. Induction of excessive activation of the unfolded protein response (UPR) is the major mechanism of PI-induced cytotoxicity in MM. The UPR is a complex transcriptional response that balances biosynthesis, folding and proteasomal destruction of cellular protein. UPR inactivation results in PI resistance in vitro, and MM cells with low UPR activation accumulate and drive the relapse in PI-resistant MM patients. Pharmacologic activation of the UPR overcomes PI-resistance in preclinical models of MM and provides an option for clinical testing. The HIV protease inhibitor nelfinavir (NFV) has UPR-inducing activity via an unknown mechanism that may involve interference with regulatory proteases in the UPR and/or proteasome activity. NFV has single agent activity in MM and sensitizes MM and AML cells for PI treatment in vitro and in vivo. Methods: We performed a multicenter phase I dose escalation study to assess safety and recommended dose for phase II of NFV in combination with bortezomib (BTZ) in patients with advanced hematologic malignancies, and to detect signals for activity. NFV was given d 1-14 twice daily p.o. at the dose levels 1250 mg (DL0), 1875 mg (DL1) and 2500 mg (DL2), BTZ was dosed 1.3 mg/m2 d 1, 4, 8, 11 i.v. in 21 day cycles. The first treatment cycle was preceded by one week of NFV monotherapy for assessment of pharmacokinetic/pharmacodynamic parameters (NFV plasma concentrations, proteasome activity and expression of UPR-related proteins in peripheral blood mononuclear cells (PBMC)). Patients were treated for 3 cycles per protocol with the option to receive up to a total of 7 cycles. Results: 12 patients were treated in the dose escalation cohort (median age 58 years; 8 patients with MM, 1 each with ALL, AML, DLBCL, MCL) for an average of 2.6 cycles. All MM patients had received prior BTZ. DLT was determined in cycle 1 in which 93 % of planned dose was delivered. One DLT was observed (G4 ALT elevation at DL2 that spontaneously resolved). Toxicity was mostly mild, could be handled symptomatically, and did not lead to study drug discontinuation except for one case of thrombocytopenia. Diarrhoea G1-2 was the most frequent toxicity observed. Ten patients were evaluable for best response while on trial therapy after having received at least one full cycle. Of these, three patients achieved a PR (1 MCL, 2 MM), 4 remained in SD for at least 2 cycles (2 MM, 1 AML, 1 ALL), while 3 progressed (2 MM, 1 DLBCL). Peak NFV plasma concentrations during monotherapy were in the dose range putatively required for UPR activation, tended to be higher in patients treated at DL1, compared to DL2 (means 13.3 vs. 8.9 mM, p=0.08) and were significantly higher during NFV monotherapy than during combination therapy with BTZ (means 9.24 vs. 6.60 mM, p=0.04), suggesting induction of NFV clearance either by autoinduction, concomitant BTZ application, or both. Pharmacodynamic analysis revealed upregulation of proteins related to UPR-induced apoptosis by NFV monotherapy in PBMC (CHOP +56%, p=0.008; PARP +57%, p=0.04, n=10). Activity of the BTZ-insensitive proteasome b2 subunit in PBMC decreased (-16%, p=0.01) during NFV monotherapy, compared to baseline, as did the BTZ-sensitive b1/b5 subunit (-17%, p=0.001). To detect additional signals for activity, an extension cohort of 6 heavily pretreated MM patients that had shown BTZ-resistance during the past 12 months and were in addition lenalidomide-resistant was treated at the recommended dose (DL2). Three of these patients achieved a PR and 2 a MR, while 1 showed PD with a mean of 4.3 cycles administered. Overall, 12 MM patients could be evaluated for best response while on therapy with BTZ + NFV in this study, of which 5 achieved a paraprotein reduction of > 50% compared to baseline (figure 1). Conclusion: Nelfinavir 2500 mg p.o. twice daily induces UPR activation and proteasome inhibition. It can safely be combined with bortezomib (1.3 mg/m2 d 1, 4, 8, 11) to potentially increase bortezomib sensitivity of hematologic malignancies. The combination yields promising clinical activity signals in patients with bortezomib-resistant myeloma. Figure 1: Best paraprotein response, relative to baseline, of evaluable patients with relapsed-refractory myeloma treated with bortezomib + nelfinavir at any dose level for at least one full cycle. Figure 1:. Best paraprotein response, relative to baseline, of evaluable patients with relapsed-refractory myeloma treated with bortezomib + nelfinavir at any dose level for at least one full cycle. Disclosures Off Label Use: the presentation will include off label use of nelfinavir as investigational medicinal product (IMP). Hitz:Celgene: Research Funding.

Safety and Efficacy of Daratumumab with Lenalidomide and Dexamethasone in Relapsed or Relapsed, Refractory Multiple Myeloma

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 84-84 ◽  
Author(s):  
Torben Plesner ◽  
Hendrik-Tobias Arkenau ◽  
Henk M. Lokhorst ◽  
Peter Gimsing ◽  
Jakub Krejcik ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Board Of Directors ◽  
Dose Escalation ◽  
Research Funding ◽  
M Protein ◽  
Open Label ◽  
Advisory Committees ◽  
Dose Escalation Study ◽  
Human Dose

Abstract Background: Daratumumab (DARA) (HuMax™-CD38), a human IgG1κ monoclonal antibody effectively mediates destruction of CD38-expressing malignant plasma cells. In the first-in-human dose-escalation study, 42% of heavily pretreated patients with relapsed, or relapsed, refractory (RR) multiple myeloma (MM) treated with DARA alone (≥4mg/kg) achieved partial response (PR) and 25% had minimal response (MR) (modified IMWG guidelines) (1). In preclinical studies, DARA + lenalidomide (LEN) enhanced killing of MM cells in vitro (2). We evaluated safety, pharmacokinetics (PK) and efficacy of DARA + LEN + low-dose dexamethasone (DEX) in patients with relapsed or RR MM. Methods: This ongoing phase I/II open-label multicenter study consisted of 2 parts: Part1 was dose-escalation study in which patients (≥ 18 years old) with life expectancy ≥3 months and ECOG status 0, 1 or 2 received DARA+LEN+DEX (DARA [2-16 mg/kg] per week [8 weeks], twice a month [16 weeks], then, once monthly until disease progression, unmanageable toxicity or 24 months in total; LEN [25 mg PO day 1 through 21 of 28-days cycles]; DEX [40 mg] once weekly). Part 2 was cohort expansion study which explored the testing of maximum tolerated DARA dose (MTD) (16 mg/kg) determined in part 1 along with LEN (25 mg mg PO day 1 through 21 of 28-days cycles) and DEX (40 mg) once weekly. Results: Data from 22 patients (13 patients [fully enrolled] from part 1 and 9 patients from part 2, [ongoing enrollment]) were presented at ASCO earlier this year (3). These results demonstrated that the most frequent (>30% patients) adverse events (AEs) were neutropenia and diarrhea; no dose limiting toxicities (DLTs) were reported. Infusion reactions (grade 1 and 2) were reported in 4 patients. 8 serious AEs were reported, all assessed as unrelated to DARA. MTD was not reached. DARA+LEN+DEX PK-profile was similar to DARA alone suggesting LEN and DEX do not affect the DARA PK-profile. Available preliminary efficacy data from 20 patients demonstrated marked decrease in M-protein in all patients; 15/20 patients achieved PR or better, 3/20 with CR, 6/20 with VGPR. Median time to response was 4.3 weeks (range: 2.1-11.3). Overall response rate (ORR) was 75% (15/20) combining all patients in part 1 and 2 and 92.3% (12/13) for part 1 patients, who had at least 2 months of follow-up or discontinued earlier. Conclusions: DARA+LEN+DEX has favorable safety profile with manageable toxicities in relapsed and RR MM. Encouraging early activity is seen with marked reduction in M-protein and majority of the patients (~75%) achieved PR or better. Results of approximately 30 patients from part 2 with at least 2 months of treatment exposure and 10 patients (out of 30 patients) with shortened duration of infusion will be presented. References Lokhorst et. al., EHA 2013 abstract #8512 van der Veer et. al., Haematologica 2011;96(2):284-90 Plesner et. al. J Clin Oncol 32:5s, 2014 (suppl; abstr 8533). Disclosures Plesner: Genmab: Consultancy; Janssen: Membership on an entity's Board of Directors or advisory committees; Celegene: Membership on an entity's Board of Directors or advisory committees. Lokhorst:Celgene: Research Funding; J&J: Research Funding; Genmab: Research Funding. Minnema:Janssen: Consultancy, Honoraria. Laubach:Onyx: Research Funding; Novartis: Research Funding; Millenium: Research Funding; Celgene: Research Funding. Ahmadi:Janssen: Employment. Yeh:Janssen: Employment. Guckert:Janssen: Employment. Feng:Janssen: Employment. Brun:Genmab: Employment. Lisby:Genmab: Employment. Basse:Genmab: Employment. Palumbo:Bristol-Myers Squibb: Consultancy, Honoraria; Genmab A/S: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen-Cilag: Consultancy, Honoraria; Millennium Pharmaceuticals, Inc.: Consultancy, Honoraria; Onyx Pharmaceuticals: Consultancy, Honoraria; Array BioPharma: Honoraria; Amgen: Consultancy, Honoraria; Sanofi: Honoraria. Richardson:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; Millennium: Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding.

Results of a Phase I Dose Escalation Study of the Novel, Oral CRM1 Selective Inhibitor of Nuclear Export (SINE) KPT-335 in Dogs with Spontaneous Non-Hodgkin's Lymphomas (NHL)

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 161-161 ◽  
Author(s):  
Sharon Shacham ◽  
Sandra Barnard ◽  
William Kisseberth ◽  
Daisuke Ito ◽  
Kiersten Jensen ◽  
...  
Keyword(s):  
Dose Escalation ◽  
Research Funding ◽  
Phase 1 ◽  
Single Agent ◽  
Large Animal ◽  
Newly Diagnosed ◽  
Dose Escalation Study ◽  
Good Tolerability ◽  
Optimal Dosing

Abstract Abstract 161 Introduction. Nuclear-cytoplasmic transport is highly regulated by karyopherin proteins – importins and exportins – through the nuclear pore complex. Of the seven known exportins, most tumor suppressor proteins (TSP) and IkB, the inhibitor of NF-kB, are transported out of the nucleus exclusively by exportin 1 (XPO1), more commonly called CRM1. SINE compounds bind irreversibly CRM1/XPO1, forcing the nuclear retention and activation of TSP and IkB, leading to selective tumor cell death. In vitro, SINEs demonstrate potent cytotoxic activity against tumor cells at nanomolar concentrations with minimal effects on normal cells in vitro. KPT-335 and related SINEs show oral bioavailability, good tolerability, and potent activity in multiple mouse xenograft models. Hematologic cancers are particularly vulnerable to SINE induced apoptosis, and effects on normal tissues are minimal at antitumor doses. Methods. Cytotoxicity was assessed in vitro with MTT and apoptosis assays. In order to evaluate the therapeutic potential of SINE in a spontaneous, large animal malignancy with many similarities to human disease including NF-kB activation, dogs with relapsed or newly diagnosed NHL were treated with KPT-335 in this dose escalation study. The primary objective was to evaluate the adverse events (AEs) and to establish the maximum tolerated dose (MTD) of KPT-335 orally in capsules. The secondary objectives were to determine the optimal dosing regimen, correlate pharmacodynamic markers and drug levels, and provide evidence of biological activity. We report the interim results defining the MTD and AEs of KPT-335 in dogs with NHL. All dogs had progressive disease (PD) on entry into the trial. Dogs with newly diagnosed or relapsed NHL, metastatic osteosarcoma (OSA), melanoma (MEL) and mast cell tumor (MCT) were eligible with preference given to NHL. The initial KPT-335 dose was 1 mg/kg (equivalent to 20mg/m2) orally with food on a Monday/Thursday schedule. At least 3 dogs were included in each cohort, and dose was escalated by 0.25mg/kg increments. CBC, serum chemistries, clotting times, drug peak plasma level and response to therapy were assessed at each weekly visit. Tumor samples will be obtained before and after treatment in an expansion cohort once the optimal dosing regimen has been determined. Results. Three structurally related SINE compounds including KPT-335 showed potent cytotoxicity of primary and immortalized canine B cell lymphomas in vitro (EC50<100 nM). The Phase 1 dose escalation study with KPT-335 oral included doses of 1mg/kg twice weekly and continued up to 2mg/kg (Table 1). Doses up to 1.75mg/kg were very well tolerated for over 3 months. At 1.75mg/kg, mild to moderate anorexia, weight loss and alkaline phosphatase elevation (possibly related to prednisone use) were observed. DLTs occurred at 2mg/kg including anorexia and vomiting without diarrhea. Laboratory parameters showed minimal or no changes at doses below the DLT. Discussion. Oral KPT-335 shows single agent disease stabilization and tumor reduction in dogs with NHL, the majority of who have diffuse large B cell lymphoma (DLBCL) relapsed after chemotherapy (typically CHOP). The activation of TSP and the neutralization of NF-kB activity by nuclear localization of IkB may contribute to the antitumor activity of SINE in canine NHL. AEs associated with drug administration include primarily anorexia, with vomiting at the DLT dose; diarrhea and significant laboratory changes were not observed. These observations are consistent with the effects of SINEs in other animal species. Conclusion. The novel SINE KPT-335 exhibits single agent biological activity with good tolerability in a relevant spontaneous large animal model of newly diagnosed and chemotherapy refractory cancer. The MTD and no adverse effect level of KPT-335 given by mouth twice weekly to dogs with NHL are ∼1.75 and 1.25 mg/kg, respectively, with anorexia, weight loss and vomiting as DLTs. Additional cohorts at doses of ≥1.25mg/kg given with increased frequency are being enrolled. These data are directly relevant to the development of oral KPT-330, a related SINE, currently in Phase 1 human clinical trials. Disclosures: Shacham: Karyopharm Therapeutics: Employment. Barnard:Karyopharm: Research Funding. Kisseberth:Karyopharm: Research Funding. Ito:Karyopharm: Research Funding. Jensen:Karyopharm: Research Funding. Borgotti:Karyopharm: Research Funding. Henson:Karyopharm: Research Funding. Wilson:Karyopharm: Research Funding. McCauley:Karyopharm Therapeutics Inc: Employment. Modiano:Karyopharm: Research Funding. Kauffman:Karyopharm Therapeutics Inc: Employment. London:Karyopharm: Research Funding.

Phase 1 Study Of The Novel Pan-Pim Kinase Inhibitor LGH447 In Patients With Relapsed/ Refractory Multiple Myeloma

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3186-3186 ◽  
Author(s):  
Marc S Raab ◽  
Enrique M. Ocio ◽  
Sheeba K. Thomas ◽  
Andreas Günther ◽  
Daniel Lebovic ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Dose Escalation ◽  
Research Funding ◽  
Kinase Inhibitor ◽  
Phase 1 ◽  
Single Agent ◽  
Hematologic Malignancies ◽  
Advisory Committees ◽  
Grade 3 ◽  
Multiple Patients

Abstract Background LGH447 is a novel, specific pan-Pim kinase inhibitor in development for the treatment of patients with multiple myeloma (MM) and other hematologic malignancies. The PIM kinase gene family encodes 3 serine/threonine protein kinases that have roles in cell cycle progression and survival. In human disease, elevated levels of Pim1 and Pim2 are associated with hematologic malignancies, with MM showing the highest level of Pim2 expression. In preclinical studies, a majority of MM cell lines proved sensitive in vitro to LGH447-mediated Pim inhibition, exhibiting a dose-dependent decrease in cell proliferation. Furthermore, LGH447 was well tolerated and demonstrated significant inhibition of tumor growth in xenograft mouse models of MM as compared with control animals, supporting the clinical development of LGH447 in MM patients. Methods Patients with relapsed/refractory MM for whom no effective treatment options exist were enrolled on this first-in-human, multicenter, open-label phase 1 dose-escalation study (CLGH447X2101). Escalating doses of single-agent LGH447 were administered orally on a continuous daily dosing schedule. Treatment continued until disease progression, unacceptable toxicity, consent withdrawal, or death. The primary objective was to estimate the maximum tolerated dose (MTD) of LGH447 administered as a single agent, orally, once daily. Secondary objectives included assessing the safety, tolerability, preliminary antimyeloma activity, and pharmacokinetic (PK) profiles of LGH447. Dose escalation followed a Bayesian logistic regression model based on dose-limiting toxicities (DLTs) occurring in cycle 1. Adverse events (AEs) were graded according to National Cancer Institute-Common Terminology Criteria for Adverse Events v4.03. Efficacy assessments were made by investigators according to International Myeloma Working Group (IMWG) uniform response criteria with modifications. Following determination of the MTD for LGH447, additional patients will be enrolled in an expansion cohort to further characterize the safety and tolerability profile of LGH447. Results At the data cutoff, 19 patients have been treated at the following doses: 70 mg (n = 5), 150 mg (n = 6), 200 mg (n = 4), 250 mg (n = 4), with enrollment ongoing in dose escalation. Median age was 66 years (range, 41-75 years). Most patients (94.7%) presented with baseline Eastern Cooperative Oncology Group performance status 0-1. Most patients (73.7%) had received ≥ 2 prior regimens (median 4; range, 1-11), 89.5% had received prior bortezomib, and 84.2% had received prior lenalidomide and/or thalidomide (68.4% and 47.4%, respectively). Ten patients are ongoing at doses between 150-250 mg, with a median duration of exposure of 6 weeks (range, 1-26.6 weeks), and 9 patients discontinued (disease progression [n = 6], AEs [n = 2], withdrawal of consent [n = 1]). There was 1 DLT consisting of grade 3 thrombocytopenia at the 200 mg dose level and no reported suspected unexpected serious AEs. The majority of AEs regardless of study drug relationship were grade 1/2. Most common grade 3/4 AEs were thrombocytopenia (31.6%), anemia (21.1%), and neutropenia (15.8%). No deaths have occurred on study. LGH447 displayed time-dependent PK with a 3- to 6-fold accumulation from day 1 to steady state (day 14). After a single oral dose, area under the curve and maximum concentration increased somewhat more than in proportion to the dose from 70 to 250 mg. Evidence of single-agent activity, as determined by investigators using IMWG criteria, has been seen in multiple patients, with best response to date being a very good partial response (VGPR). Conclusion In heavily treated patients with relapsed/refractory MM, LGH447 was generally well tolerated and exhibited evidence of single-agent efficacy in multiple patients, validating Pim kinase inhibition as a promising therapeutic rationale and supporting its further clinical development in patients with MM and other hematologic malignancies. Dose escalation is ongoing and updated results will be presented. Disclosures: Ocio: BMS: Consultancy; Arry-520: Consultancy; Pharmamar: Research Funding; Celgene: Honoraria, Research Funding; Onyx: Consultancy, Research Funding; Novartis: Honoraria. Thomas:Novartis: Research Funding; Celgene: Research Funding; Immunomedics: Research Funding; Pharmacyclics: Membership on an entity’s Board of Directors or advisory committees; Onyx: Membership on an entity’s Board of Directors or advisory committees; Millenium: Research Funding. Günther:Novartis: Consultancy, Research Funding. Lebovic:Celgene: Speakers Bureau; Allos/Spectrum: Speakers Bureau; Genentech: Speakers Bureau; Onyx: Speakers Bureau. Kumar:Onyx: Consultancy, Research Funding; Millennium: Consultancy, Research Funding; Celgene: Consultancy, Research Funding. Jakubowiak:Onyx: Consultancy, Honoraria, Speakers Bureau; Millennium: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Speakers Bureau; BMS: Consultancy, Honoraria. Song:Novartis: Employment. Xiang:Novartis: Employment. Hynds:Novartis: Employment. Vanasse:Novartis: Employment. Goh:Jannsen: Research Funding; BMS: Membership on an entity’s Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Hospira: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding.

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