Novel AKT Inhibitor GSK2110183 Shows Favorable Safety, Pharmacokinetics, and Clinical Activity in Multiple Myeloma. Preliminary Results From a Phase I First-Time-In-Human Study

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1856-1856 ◽  
Author(s):  
Andrew Spencer ◽  
Sung-Soo Yoon ◽  
Simon J. Harrison ◽  
Shannon Morris ◽  
Deborah Smith ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Acute Leukemia ◽  
Phase I ◽  
Research Funding ◽  
Human Study ◽  
B Cell Lymphoma ◽  
Clinical Activity ◽  
Akt Inhibitor ◽  
Serum Lipase ◽  
Heavily Pretreated

Abstract Abstract 1856 Background: Despite significant progress in treatment, multiple myeloma (MM) remains an incurable disease. There is a well recognized need for new agents with novel mechanisms of action, which would complement currently available drugs. The PI3K/AKT pathway is constitutively active in MM, providing proliferative and anti-apoptotic signals and possibly contributing to resistance to treatment. Therefore, AKT is a potential pharmacologic target in MM. GSK2110183 is a potent, orally available, ATP competitive inhibitor of all three isoforms of AKT. Methods: We conducted a phase I study to define the maximum tolerated dose (MTD) and to evaluate the PK, PD and clinical activity in patients with advanced hematologic malignancies. This two-part study consisted of dose escalation (Part1) followed by expansion in selected malignancies (Part2) to evaluate safety and clinical activity at the MTD. GSK2110183 was administered continuously once daily until unacceptable toxicity or disease progression. Results: Preliminary data are available for 73 patients who have received >1 dose of GSK2110183. Patients had the following malignancies: Non-Hodgkin's Lymphoma (NHL, 14), Hodgkin lymphoma (HL, 8), chronic lymphocytic leukemia (CLL 7), MM (34), acute leukemia (10). In Part1 GSK2110183 was administered at daily doses of 25mg, 75mg, 100mg, 125mg and 150mg. Dose limiting toxicities (DLTs) were observed in 3 of 6 patients at 150mg, thereby defining the MTD as 125mg daily. DLTs at 150mg were: short term memory loss (n=1) and elevation of AST/ALT accompanied by AP and bilirubin elevations (n=2). One of the two patients with liver toxicities also had serum lipase and amylase elevations. DLTs were reversible upon drug discontinuation in two patients. The third patient had diffuse large B cell lymphoma with hepatic involvement, which led to persistent liver enzyme elevations. The most common observed drug-related adverse events for all patients (>10%) were: nausea (20%), diarrhea (16%), dyspepsia (15%), fatigue (15%), anorexia (12%) and gastrointestinal reflux disease (11%). Observed grade 3 drug related hematologic toxicities were: neutropenia (n=4), and thrombocytopenia (n=1). No grade 4 hematologic toxicities were observed. In general, therapy was well-tolerated, with subjects continuing on therapy for up to 21 months. Mean AUC(0–24) and Cmax values increased with increasing doses; however, there was variability among subjects. Median Tmax across doses was 2 hrs, and the mean t 1/2 was approximately 1.7 days. GSK2110183 accumulated 1.4 to 5.1-fold with repeat daily dosing. Median (range) duration of treatment for different types of malignancies was as follows: NHL 88.5 days (12–597), HL 266 days (38–478), CLL 64 days (1–546), MM 87 days (8–323) and acute leukemia 37days (22–85). Subjects with MM were the main focus of the expansion cohort to evaluate for preliminary signals of efficacy. A total of 32 heavily pretreated, relapsed/refractory MM patients were treated at the 125mg dose, achieving an overall response rate of 19% (3 PR, 3 MR). All but one responder had prior treatment with proteasome inhibitor (PI), immunomodulatory agents (IMID) and alkylating agents. Responders were as equally heavily pretreated as the non-responders, with a median of 5 prior lines of treatment (range 2–8). Most significant reductions in M protein occurred very early in the treatment course (4/6 within 21 days). The respective mean (range) duration on study treatment for those who achieved MR or PR was 216 days (105–315), for subjects achieving stable disease 117 days (84–147), and for subjects with progressive disease 52 days (15–105). Conclusions: The AKT inhibitor GSK2110183 is well tolerated and demonstrates clinical activity as monotherapy in heavily pretreated MM patients. Further work is ongoing to identify the patients who are most likely to respond to AKT inhibition, as well as to define the most rational combination of the AKT inhibitor with other agents in order to maximize the clinical benefit for MM patients. Disclosures: Spencer: GSK: Honoraria, Research Funding. Yoon:GSK: Honoraria. Harrison:GSK: Honoraria, Research Funding. Morris:GSK: Employment. Smith:GSK: Employment. Freedman:GSK: Employment. Brigandi:GSK: Employment. Oliff:GSK: Employment. Opalinska:GlaxoSmithKline: Employment. Chen:GSK: Research Funding.

A Phase I/II Trial of the KSP Inhibitor ARRY-520 In Relapsed/Refractory Multiple Myeloma

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1959-1959 ◽  
Author(s):  
Jatin J Shah ◽  
Jeffrey A. Zonder ◽  
Adam Cohen ◽  
Donna Weber ◽  
Sheeba Thomas ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Dose Escalation ◽  
Research Funding ◽  
Phase 1 ◽  
Single Agent ◽  
Clinical Activity ◽  
Employment Equity ◽  
Heavily Pretreated ◽  
Equity Ownership ◽  
Ksp Inhibitor

Abstract Abstract 1959 Background: Kinesin Spindle Protein (KSP) is required for cell cycle progression through mitosis. Inhibition of KSP induces mitotic arrest and cell death. ARRY-520 is a potent, selective KSP inhibitor. Cancers such as multiple myeloma (MM) which depend on the short-lived survival protein MCL-1 are highly sensitive to treatment with ARRY-520. ARRY-520 shows potent activity in preclinical MM models, providing a strong rationale for its clinical investigation in this disease. Methods: This Phase 1 study was designed to evaluate the safety and pharmacokinetics (PK) of ARRY-520 administered intravenously (IV) on Day 1 and Day 2 q 2 weeks without/with granulocyte-colony stimulating factor (G-CSF). Patients (pts) with relapsed/refractory (RR) MM with 2 prior lines of therapy (including both bortezomib and an immunomodulatory agent, unless ineligible for or refusing to receive this therapy) were eligible. Cohorts of at least 3 pts were enrolled in a classical 3 + 3 dose escalation design. Pts were treated for 2 cycles (4 weeks) to evaluate safety prior to dose escalation. Results: Twenty five pts have been treated to date, with a median age of 60 years (range 44–79) and a median of 5 prior regimens (range 2–16). All pts received prior bortezomib or carfilzomib, 21 pts received prior lenalidomide, 17 pts prior thalidomide, and 18 pts had a prior stem cell transplant. Pts received ARRY-520 without G-CSF at 1 mg/m2/day (n = 3), and at 1.25 mg/m2/day (n = 7, 6 evaluable). A dose-limiting toxicity (DLT) of Grade 4 neutropenia was observed at 1.25 mg/m2/day, and this was considered the maximum tolerated dose (MTD) without G-CSF. As neutropenia was the DLT, dose escalation with prophylactic G-CSF support was initiated, at doses of 1.5 mg/m2/day (n = 7, 6 evaluable), 2.0 mg/m2/day (n = 6) and 2.25 mg/m2/day (n = 2) with G-CSF. Both the 2.0 mg/m2/day and 2.25 mg/m2/day dose levels were determined to be non-tolerated, with DLTs of febrile neutropenia (FN) (2 pts at 2.0 mg/m2/day and both pts at 2.25 mg/m2/day) and Grade 3 mucositis (both pts at 2.25 mg/m2/day). One out of 6 evaluable pts at 1.5 mg/m2/day also developed a DLT of FN. In an attempt to optimize the Phase 2 dose, an intermediate dose level of 1.75 mg/m2/day with G-CSF is currently being evaluated. The most commonly reported treatment-related adverse events (AEs) include those observed with other KSP inhibitors, such as hematological AEs (thrombocytopenia, neutropenia, anemia, leukopenia), fatigue, mucositis and other gastro-intestinal AEs. Pts displayed linear PK, a low clearance and a moderate volume of distribution, with moderate-to-high inter-individual variability in PK parameters. The median terminal elimination half life is 65 hours. The preliminary efficacy signal as a single agent is encouraging with 2 partial responses (PR) observed to date per IMWG and EBMT criteria in a heavily pretreated population (23 evaluable pts). A bortezomib-refractory pt with 8 prior lines of therapy, including a tandem transplant, treated at 1 mg/m2/day of ARRY-520 obtained a PR after Cycle 6, with urine protein and kappa light chain levels continuing to decline over time. He remains on-study after 15 months of ARRY-520 treatment. A pt with 2 prior lines of therapy, including prior carfilzomib, has obtained a PR after Cycle 8 at 2 mg/m2/day of ARRY-520, and she is currently ongoing after 4.5 months on therapy. Fifteen pts had a best response of stable disease (SD), including 1 pt with a thus far unconfirmed minimal response, and 6 had progressive disease. A total of 10 pts (43%) achieved a PR or SD lasting > 12 weeks. Several additional pts have shown other evidence of clinical activity, with decrease in paraproteins, increase in hemoglobin levels and regression of plasmacytomas. The median number of cycles is 4 (range 1–28+). Treatment activity has not correlated with any baseline characteristics or disease parameters to date. Conclusions: : The selective KSP inhibitor ARRY-520 has been well tolerated, and shows promising signs of single agent clinical activity in heavily pretreated pts with RR MM. Prophylactic G-CSF has enabled higher doses to be tolerated. No cardiovascular or liver enzyme toxicity has been reported. Enrollment is ongoing at 1.75 mg/m2/day with G-CSF support, and a planned Phase 2 part of the study will be initiated as soon as the MTD is determined. Complete Phase 1 data will be disclosed at the time of the meeting. Disclosures: Shah: Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium: Research Funding. Off Label Use: Revlimid (lenalidomide) in combination with dexamethasone is indicated for the treatment of multiple myeloma patients who have received at least one prior therapy. Zonder:Millennium: Consultancy, Myeloma and Amyloidosis Patient Day Symposium – Corporate support from multiple sponsors for a one-day educational event, Research Funding; Celgene:; Novartis:; Proteolix: . Weber:novartis-unpaid consultant: Consultancy; Merck- unpaid consultant: Consultancy; celgene- none for at least 2 years: Honoraria; millenium-none for 2 years: Honoraria; celgene, Millenium, Merck: Research Funding. Wang:Celgene: Research Funding; Onyx: Research Funding; Millenium: Research Funding; Novartis: Research Funding. Kaufman:Celgene: Consultancy, Honoraria, Research Funding; Millenium: Consultancy, Honoraria; Merck: Research Funding; Genzyme: Consultancy. Walker:Array Biopharma: Employment, Equity Ownership. Freeman:Array Biopharma: Employment, Equity Ownership. Rush:Array Biopharma: Employment, Equity Ownership. Ptaszynski:Array Biopharma: Consultancy. Lonial:Millennium, Celgene, Bristol-Myers Squibb, Novartis, Onyx: Advisory Board, Consultancy; Millennium, Celgene, Novartis, Onyx, Bristol-Myers Squibb: Research Funding.

Safety, pharmacokinetics (PK), pharmacodynamics (PD), and clinical activity of the oral AKT inhibitor GSK2141795 (GSK795) in a phase I first-in-human study.

2011 ◽  
Vol 29 (15_suppl) ◽  
pp. 3003-3003 ◽  
Author(s):  
H. A. Burris ◽  
L. L. Siu ◽  
J. R. Infante ◽  
J. J. Wheler ◽  
C. Kurkjian ◽  
...  
Keyword(s):  
Phase I ◽  
Human Study ◽  
Clinical Activity ◽  
Akt Inhibitor

Phase I study of TH-302, an investigational hypoxia-targeted drug, and dexamethasone in patients with relapsed/refractory multiple myeloma.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 8602-8602
Author(s):  
Irene M. Ghobrial ◽  
Jacob Laubach ◽  
Philippe Armand ◽  
Erica Boswell ◽  
Courtney Hanlon ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Phase I ◽  
Clinical Activity ◽  
Heavily Pretreated ◽  
Hepatorenal Function ◽  
Definition Of ◽  
Ecog Ps

8602 Background: TH-302 is an investigational 2-nitroimidazole prodrug of the DNA alkylator Br-IPM designed to be selectively activated in hypoxia. In multiple myeloma (MM) mouse models, diseased animals demonstrate a marked expansion of areas of hypoxia in the bone marrow. TH-302 exhibited anti-tumor activity against MM in vitro and in vivo and synergism was seen when combined with bortezomib (Hu et al, Blood 2010; Chesi et al, Blood 2012). Based on these findings, a phase I/II study of TH-302 plus dexamethasone (dex) was initiated for patients (pts) with relapsed/refractory MM. Methods: Eligible pts in the study (NCT01522872) had ECOG PS ≤ 2, receipt of at least two prior therapies, and acceptable hepatorenal function and hematologic status. A standard 3+3 dose escalation design was used with a fixed oral 40 mg dose of dex and 40% dose increments of TH-302. TH-302 was administered IV with dex on days 1, 4, 8, and 11 of a 21-day cycle. The objectives were to determine DLTs and the MTD; assess the safety, tolerability and preliminary clinical activity of TH-302 plus dex; and study the relationship between hypoxia within the bone marrow and response to TH-302. Results: Eleven pts have been treated: 7M/4F with a median age 61 years (range: 53 – 86) and 6 prior therapies (range: 3 – 10). All received both bortezomib and lenalidomide/thalidomide containing regimens. TH-302 was dosed at 240 (n=5), 340 (n=4), and 480 (n=2) mg/m² for a median of 5 cycles. No DLTs were reported at 240 or 340 mg/m². Two pts treated at 480 mg/m² had DLTs of grade 3 mucositis, exceeding the definition of MTD. A dose expansion is thus ongoing at 340 mg/m2. Two patients had SAEs related to TH-302 (pneumonia). Five pts continue on study after a median of 7 cycles (range: 2–11). Nine pts have had efficacy evaluations: 2 pts with partial responses, 2 pts with minimal responses, and 5 pts with stable disease, for an overall response rate (of MR or better) of 44%. Conclusions: TH-302 can be administered at 340 mg/m2 biweekly + dex, with dose limiting mucositis seen at higher doses. Initial clinical activity has been noted with an ORR of 44% in heavily pretreated MM pts who are relapsed/refractory to both bortezomib and lenalidomide. Clinical trial information: NCT01522872.

Imexon (AOP 99.0001) for Treatment of Relapsed or Refractory Multiple Myeloma: A Phase I/II Study

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 5195-5195
Author(s):  
Thomas M. Moehler ◽  
Anatoli Golenkov ◽  
Heinz Ludwig ◽  
Martin H Kropff ◽  
Nuriet K Khuageva ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Phase I ◽  
Dose Range ◽  
Parent Compound ◽  
Single Agent ◽  
Objective Response ◽  
Study Drug ◽  
B Cell Lymphoma ◽  
Clinical Activity ◽  
Duration Of Treatment

Abstract Background: Imexon (AOP 99.0001 (4-imino-1,3-diazobicyclo-(3, 1, 0)-hexan-2-one) exerts antiproliferative activity on a range of tumor cells including myeloma cells and was found to inhibit tumor development in murine models of B-cell lymphoma. The antitumor activity of Imexon is caused by a sequence of molecular events starting with alkylation of thiol groups, reduction of the intracellular antioxidative defence mechanism, increase of reactive oxygen species (ROS) in mitochondria, and mitochondrial damage and induction of apoptosis. Methods/Patients: 36 patients with relapsed or refractory myeloma who had been pretreated with at least two lines of prior therapy were included. Imexon was applied as a 15-min infusion on 5 consecutive days for 2 weeks (d1–5 and d8–12) with a rest period of one week (1 cycle). Escalation of the dose of Imexon was started with 50 mg/m2 during the phase I part of the study. Results: The plasma half life of the parent compound and its active metabolite Imexon was found to be approximately 1.2 hrs and 2.6 hrs, respectively. The mean duration of treatment with Imexon was 6.8 weeks in a dose range between 50 and 1000 mg/m2 without reaching dose limiting toxicity. Drug related grade 1–2 AEs occurring with a frequency of >10 % were fatigue, nausea, constipation, headache, anorexia, muscle/bone pain, anemia, thrombocytopenia, leucopenia and transient elevation of GGT Grade 3–4 AEs related to study drug were leucopenia (n=3), anemia (n=2), thrombocytopenia (n=4), osteonecrosis (n=1), creatinine increase (n=1). In two patients dose reductions due to AEs were required. A total of 7 SAEs occured in 4 patients. All SAEs occurred at the 400 mg/m2 DL 1 SAE (increase in creatinine) was considered to be related to study drug. There was no correlation between the dose of the study drug and AEs. In addition, no mortality was encountered while patients were on treatment with Imexon. Imexon treatment resulted in a minimal response in one patient at the DL of 500 mg/m2. In addition, a significant improvement of the preexisting distal polyneuropathy was noted in this patient during these first 3 therapy cycles. After discontinuation of Imexon, reappearance of the polyneuropathy was noted within 4 months. This led to retreatment of the patient at a dose level of 600 mg/m2, which resulted in a gradual and finally complete resolution of the polyneuropathy with maintenance of the MR, but without further reduction in the mIg. No other objective response was observed in this study. Conclusion: Overall, Imexon was safe and well tolerated in the dose range investigated. Imexon demonstrated only minor clinical activity in one patient. These results do not support the further development of Imexon as single agent in multiple myeloma. Due to its unique mechanism of action and its favourable toxicity profile it may, however, qualify for use and evaluation in combination with other agents in multiple myeloma and other malignancies.

BT062, An Antibody-Drug Conjugate Directed Against CD138, Shows Clinical Activity in Patients with Relapsed or Relapsed/Refractory Multiple Myeloma

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 305-305 ◽  
Author(s):  
Sundar Jagannath ◽  
Asher Chanan-Khan ◽  
Leonard T. Heffner ◽  
David Avigan ◽  
Todd M. Zimmerman ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Adverse Events ◽  
Phase I ◽  
Board Of Directors ◽  
Research Funding ◽  
Clinical Activity ◽  
Antibody Drug Conjugate ◽  
Advisory Committees ◽  
Dose Levels ◽  
Antibody Drug

Abstract Abstract 305 Background: CD138 (Syndecan-1) is highly overexpressed in various solid tumors and hematological malignancies and represents one of the most specific target antigens for identification of multiple myeloma (MM) cells. BT062 (Biotest AG Dreieich, Germany) is an antibody-drug conjugate, comprised of the anti-CD138 chimerized MAb (nBT062) and the cytotoxic agent DM4. Once bound to CD138 on a target cell, the conjugate is internalized and releases DM4, leading to target cell death. We performed the first in man study (969) to investigate safety and efficacy of BT062 in MM. Objectives: To determine the maximum tolerated dose (MTD), the dose-limiting toxicities (DLTs), pharmacokinetics (PK) and anti-MM activity of increasing doses of BT062 on a repeated single dose schedule once every three weeks in patients with relapsed and/or refractory MM. Methods: This is a prospective, open label, dose-escalation, multicenter phase I study. Patients aged ≥18 years with relapsed or relapsed/refractory MM who have failed previous treatments including an immunomodulatory agent and a proteasome inhibitor were eligible to participate. Patients with clinical response (or no evidence of progressive disease) and without unacceptable toxicities were eligible for further treatment cycles. Patients were enrolled in cohorts of 3 at each dose level, with DLT in the first cycle triggering cohort expansion. Toxicities were assessed by CTCAE v3 and clinical response was assessed according to the international myeloma working group criteria. Results: A total of 32 patients have been treated with BT062, receiving one of 7 dose levels ranging from 10 mg/m2 to 200 mg/m2. Maximum administered dose has been defined at 200 mg/m2, with mucositis as the dose limiting toxicity (CTC grade III in 2 of the 3 patients in this cohort). Thirteen of 32 patients have been treated in an expanded MTD-cohort at 160 mg/m2. The most frequently reported adverse events to date are mild to moderate and cover primarily events expected for the underlying disease and patient group. A few adverse events have also been observed involving skin and/or mucosa (tissues of epithelial origin with CD138 expressing cells), as well as the eye. CTC grade II/III toxicity involving skin and/or mucosa (e.g. mucositis, stomatitis, hand/foot syndrome) has been observed mainly at the dose levels 160 mg/m2 or higher. Adverse events involving the eye (e.g. blurred vision, dry eye) have also been reported mainly in patients at the dose levels 160 mg/m2 or higher, all restricted to CTC grade I/II. Among the 27 evaluable patients, 3 patients responded including 1 partial response and 2 minor responses, with one patient (minor response) remaining on treatment for more than a year. Stabilization of disease was noted in an additional 11 patients, receiving a median of 5 cycles of therapy (range of 4–10). Thus stable disease or better was noted in 52% of patients. Most patients came off study due to disease progression. Conclusion: Preliminary data from this study demonstrate an acceptable toxicity profile of BT062. Even in this phase I patient population, evidence of clinical activity was observed. Based on the favourable safety profile, the pharmacokinetic data and early signs of clinical activity, a Phase I/IIa study in MM (975) is initiated to further evaluate the safety and anti-MM efficacy of BT062 in a more frequent dosing regimen. To date 13 patients have been treated with BT062 on the intensified multi-dose regimen, receiving one of the first four dose levels. Updated results on safety, PK and anti-MM efficacy of BT062 will be presented. Disclosures: Jagannath: Celgene: Honoraria; Millennium/Takeda Pharma: Honoraria; J&J Family: Honoraria; Onyx: Honoraria; Merck: Honoraria. Heffner:Millennium: Research Funding. Avigan:Genzyme: Consultancy, Research Funding; Celgene: Research Funding; Curetec: Research Funding. Lutz:ImmunoGen, Inc.: Employment. Engling:Biotest AG: Employment. Uherek:Biotest AG: Employment. Osterroth:Biotest AG: Employment. Ruehle:Biotest AG: Employment. Beelitz:Biotest Pharmaceuticals Corporation: Employment. Niemann:Biotest AG: Employment. Wartenberg-Demand:Biotest AG: Employment. Haeder:Biotest AG: Employment. Anderson:Merck: Consultancy; Onyx: Consultancy; Novartis: Consultancy; Celgene: Consultancy; Millennium Pharmaceuticals, Inc.: Consultancy; Bristol-Myers Squibb: Consultancy; Actelion: Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Munshi:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

scholarly journals Initial Clinical Activity of FT596, a First-in-Class, Multi-Antigen Targeted, Off-the-Shelf, iPSC-Derived CD19 CAR NK Cell Therapy in Relapsed/Refractory B-Cell Lymphoma

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 8-8
Author(s):  
Veronika Bachanova ◽  
Zuzan Cayci ◽  
Dixie Lewis ◽  
Joseph E. Maakaron ◽  
Murali Janakiram ◽  
...  
Keyword(s):  
Cell Therapy ◽  
Phase I ◽  
B Cell ◽  
Board Of Directors ◽  
Research Funding ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Clinical Activity ◽  
Publicly Traded ◽  
Advisory Committees

Induced pluripotent stem cell (iPSC)-derived immune effector cells offer distinct advantages over existing patient- and donor-derived therapeutic approaches, including the use of a clonal master engineered iPSC line as a renewable source for the mass production of immune cells, which are available off-the-shelf for broad patient access. FT596 is an investigational, off-the-shelf, multi-antigen targeting, chimeric antigen receptor (CAR) natural killer (NK) cell therapy derived from a human clonal master iPSC line engineered with three anti-tumor modalities: (1) a proprietary CD19-targeting CAR; (2) a novel high-affinity, non-cleavable CD16 Fc receptor that enables tumor targeting and enhanced antibody-dependent cell cytotoxicity in combination with a therapeutic monoclonal antibody (mAb); and (3) interleukin (IL)-15/IL-15 receptor fusion promoting cytokine-autonomous persistence. Preclinical in vivo models demonstrate potent multi-antigen targeting activity of FT596 against both CD19+ and CD19- tumor cell lines when combined with the anti-CD20 agent rituximab (Goodridge et al. 2019). FT596 is currently being investigated as a monotherapy and in combination with the anti-CD20 mAbs rituximab and obinutuzumab in a multicenter, Phase I clinical trial for the treatment of relapsed/refractory B-cell lymphoma and chronic lymphocytic leukemia. The trial will test up to four FT596 dose levels ranging from 30 to 900 million cells. We describe the demonstration of early clinical benefit of FT596 in a patient who received a single administration of FT596 as a monotherapy at the first dose level in the Phase I trial. The patient is a 76-year-old female with diffuse large B-cell lymphoma, germinal center B-cell subtype, who was initially diagnosed in January 2014. The patient received eight prior treatment regimens, including autologous stem cell transplant, rituximab in combination with engineered autologous T cells expressing antibody-coupled T-cell receptor, and, most recently, was refractory to an experimental combination therapy comprised of lymphodepleting chemotherapy followed by ex vivo expanded allogeneic NK cells, IL-2, and rituximab. The patient received fludarabine and cyclophosphamide lympho-conditioning followed by a single administration of 30 million cells of FT596 as monotherapy. During the 28-day follow-up period for safety, no dose-limiting toxicities were observed. No cytokine release syndrome, neurologic toxicity, or graft-versus-host disease of any grade was observed. Grade ≥3 treatment-emergent adverse events (AEs) included decreased white blood cell count, decreased neutrophil count, anemia, urinary tract infection with neutropenic fever, and hypertension. Notably, none of these AEs were considered related to FT596 by the treating investigator physician, except for decreased neutrophil count, which was considered possibly related to FT596 and resolved. Evidence of hematologic recovery was observed by the end of the 28-day follow-up safety period. On Study Day 29, the patient's tumor response assessment showed partial response by Lugano 2014 criteria, with a greater than 70% decrease in 18F-fluorodeoxyglucose uptake and greater than 50% reduction in tumor size. The patient remains on study and, per protocol and in collaboration with the U.S. Food and Drug Administration, is being considered for retreatment with a second cycle of FT596 monotherapy. This is the first-ever demonstration of clinical activity following treatment with an off-the-shelf, iPSC-derived CAR immune cell therapy and provides direct evidence that low doses of FT596 can induce short-term responses, opening the opportunity for multi-dosing strategies to deepen response and duration. Additional clinical, pharmacokinetic, and pharmacodynamic data from this patient will be provided at the time of the meeting. The Phase I trial is ongoing and is registered on clinicaltrials.gov: NCT04245722. Disclosures Bachanova: FATE: Research Funding; Kite: Membership on an entity's Board of Directors or advisory committees; Karyopharma: Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; Gamida Cell: Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Research Funding. Janakiram:Takeda, Fate, Nektar: Research Funding. Payne:Fate Therapeutics: Current Employment, Current equity holder in publicly-traded company. Wong:Fate Therapeutics: Current Employment, Current equity holder in publicly-traded company. Cooley:Fate Therapeutics: Current Employment, Current equity holder in publicly-traded company. Valamehr:Fate Therapeutics, Inc: Current Employment, Current equity holder in publicly-traded company. Chu:Fate Therapeutics, Inc.: Current Employment, Current equity holder in publicly-traded company; Roche Holding AG: Current equity holder in publicly-traded company. Miller:GT Biopharma: Consultancy, Patents & Royalties, Research Funding; Vycellix: Consultancy; Onkimmune: Honoraria, Membership on an entity's Board of Directors or advisory committees; Nektar: Honoraria, Membership on an entity's Board of Directors or advisory committees; Fate Therapeutics, Inc: Consultancy, Patents & Royalties, Research Funding. OffLabel Disclosure: Cyclophosphamide and fludarabine will be used as lympho-conditioning therapy prior to FT596 administration.

Combination of Bendamustine, Lenalidomide, and Dexamethasone In Patients with Refractory or Relapsed Multiple Myeloma Is Safe and Highly Effective: Results of a Phase I Clinical Trial

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 989-989
Author(s):  
Suzanne Lentzsch ◽  
Amy O'Sullivan ◽  
Ryan Kennedy ◽  
Navkiranjit Gill ◽  
Carrie Andreas ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Overall Survival ◽  
Phase I ◽  
Dose Level ◽  
Research Funding ◽  
Phase I Trial ◽  
Clinical Activity ◽  
Grade 3 ◽  
Expansion Cohort ◽  
Level 2

Abstract Abstract 989 Background: Lenalidomide is an analog of thalidomide that has significant clinical activity in combination with dexamethasone in patients with relapsed or refractory multiple myeloma (MM). Bendamustine is a bifunctional alkylating agent that is approved for the treatment of chronic lymphocytic leukemia and indolent non-Hodgkin's lymphoma that has progressed during or relapsed within 6 months following a rituximab-containing regimen. This multicenter phase I trial is the first to investigate the combination of bendamustine, lenalidomide, and dexamethasone. Our primary objective was to determine the maximum tolerated dose (MTD) and safety profile of bendamustine and lenalidomide when administered with dexamethasone for patients with relapsed or refractory MM. Methods: Patients aged ≥18 years with confirmed, measurable symptomatic MM that was refractory to or progressed after 1 or more prior therapies were treated with bendamustine by intravenous infusion on days 1 and 2, oral lenalidomide on days 1–21, and oral dexamethasone on days 1, 8, 15, and 22 of each 28-day cycle. Treatment was continued until a plateau or best response, as determined by the International Myeloma Working Group uniform response criteria, was reached. Study drug doses were escalated through 3 levels (Table 1) in a 3+3 dose-escalation scheme. The MTD was defined as the dose level at which ≤1 of 6 patients experienced dose-limiting toxicity (DLT) during the first cycle of therapy when the next higher dose level is associated with DLTs in ≥2 patients. After determining the MTD, an expansion cohort of 12 additional patients at the MTD will be treated to better evaluate toxicity and clinical activity. Secondary endpoints included preliminary efficacy as evidenced by objective response, time to disease progression, and overall survival. Results: Twenty-six patients with a median age of 63 years (range, 38 to 81 years) were enrolled. The mean number of prior therapies was 3 (range, 2–7); 81% of the patients had prior lenalidomide, 48% had prior thalidomide, and 29% had both. The MTD was identified at dose level 2: 75 mg/m2 bendamustine and 10 mg lenalidomide. Four DLTs were recorded: at dose level 2 (n = 6), 1 patient with grade 4 neutropenia; at dose level 3 (n = 6), 2 patients with grade 4 neutropenia and another with delayed platelet recovery from grade 3 thrombocytopenia. Currently 9 patients have been enrolled in the expansion cohort. Twenty-one of 26 patients received at least 2 cycles and were included in the response assessment. A partial response (PR) or better was observed in 63% (n = 12) of the patients, including 16% (n = 3) achieving a very good PR (VGPR). In addition to these 12 patients, another 3 (15%) had a minor response (25%-49% reduction in M-protein). Stable disease was observed in 32% (n = 6), and only 5% (n = 1) had disease progression. The median time to next treatment was 8.1 months (range, 1.9–27.3 months). Other grade 3/4 adverse events occurring after the first cycles of treatment included prolonged QTc in 1 patient. Conclusions: This is the first phase I trial testing the combination of bendamustine, lenalidomide, and dexamethasone for relapsed and refractory MM. This regimen is well tolerated even in older patients up to 81 years. With a PR/VGPR rate of 63%, this combination is a highly active regimen even in heavily pretreated MM patients, and its side effect profile makes it an attractive treatment option for MM patients especially with pre-existing therapy-related peripheral sensory neuropathy. Final data on response and overall survival will be available at the time of presentation. Disclosures: Lentzsch: Celgene Corp: Research Funding. Roodman:Amgen, Novartis, Celgene, Acceleron: Consultancy. Zonder:Amgen, Celgene, Cephalon: Consultancy; Millennium: Research Funding; Millennium: CME only, no promotional work.

scholarly journals Phase I and Pharmacologic Study of SNS-032, a Potent and Selective Cdk2, 7, and 9 Inhibitor, in Patients With Advanced Chronic Lymphocytic Leukemia and Multiple Myeloma

2010 ◽  
Vol 28 (18) ◽  
pp. 3015-3022 ◽  
Author(s):  
Wei-Gang Tong ◽  
Rong Chen ◽  
William Plunkett ◽  
David Siegel ◽  
Rajni Sinha ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Chronic Lymphocytic Leukemia ◽  
Phase I ◽  
Clinical Efficacy ◽  
Stable Disease ◽  
Single Agent ◽  
Tumor Lysis Syndrome ◽  
Lymphocytic Leukemia ◽  
Clinical Activity ◽  
Dose Escalation Study

Purpose SNS-032 is a highly selective and potent inhibitor of cyclin-dependent kinases (Cdks) 2, 7, and 9, with in vitro growth inhibitory effects and ability to induce apoptosis in malignant B cells. A phase I dose-escalation study of SNS-032 was conducted to evaluate safety, pharmacokinetics, biomarkers of mechanism-based pharmacodynamic (PD) activity, and clinical efficacy. Patients and Methods Parallel cohorts of previously treated patients with chronic lymphocytic leukemia (CLL) and multiple myeloma (MM) received SNS-032 as a loading dose followed by 6-hour infusion weekly for 3 weeks of each 4-week course. Results There were 19 patients with CLL and 18 with MM treated. Tumor lysis syndrome was the dose-limiting toxicity (DLT) for CLL, the maximum-tolerated dose (MTD) was 75 mg/m2, and the most frequent grade 3 to 4 toxicity was myelosuppression. One patient with CLL had more than 50% reduction in measurable disease without improvement in hematologic parameters. Another patient with low tumor burden had stable disease for four courses. For patients with MM, no DLT was observed and MTD was not identified at up to 75 mg/m2, owing to early study closure. Two patients with MM had stable disease and one had normalization of spleen size with treatment. Biomarker analyses demonstrated mechanism-based PD activity with inhibition of Cdk7 and Cdk9, decreases in Mcl-1 and XIAP expression level, and associated CLL cell apoptosis. Conclusion SNS-032 demonstrated mechanism-based target modulation and limited clinical activity in heavily pretreated patients with CLL and MM. Further single-agent, PD-based, dose and schedule modification is warranted to maximize clinical efficacy.

High Dose Zevalin (90Yttrium Ibritumomab Tiuxetan) Treatment with PBSC Support in Refractory-Resistant NHL Patients: Preliminary Results of a Phase I/II Study.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 488-488 ◽  
Author(s):  
Anna Vanazzi ◽  
Pierfrancesco Ferrucci ◽  
Mahila Ferrari ◽  
Liliana Calabrese ◽  
Marta Cremonesi ◽  
...  
Keyword(s):  
Phase I ◽  
Median Time ◽  
Dose Intensity ◽  
Median Number ◽  
Therapeutic Options ◽  
Clinical Activity ◽  
High Dose ◽  
Resistant Refractory ◽  
Duration Of Response ◽  
Heavily Pretreated

Abstract Therapeutic options are limited for resistant-refractory high-grade NHL pts not suitable to HDCT or for those pts relapsing after ABMT. Zevalin has been already demonstrated active in elderly pts with resistant-primary refractory DLBCL at dose of 0.4 mCi/kg, however duration of response is short. Increasing RIT dose intensity might improve efficacy. There are no data about the use of Zevalin at myeloablative dosage. We present feasibility and toxicity results of a phase I/II study of HD-Zevalin with PBSC support in resistant-refractory NHL pts. Three Zevalin dose-levels were fixed: 0.8, 1.2, 1.5 mCi/kg; from April 2004 to July 2005 12pts were enrolled, 4pts at each dose level. Median age was 66,5 ys (28–73), 83% male. All pts had stage III/IV at diagnosis; 7DLBCL; 3MCL, 1FL, 1transformed MZL. 7pts had received more than 3 previous CT regimens. All pts had received prior rituximab, 3pts RT, 6pts HD-CT. BM was negative in all pts before RIT. 1Week prior to Zevalin all pts underwent dosimetry and if no abnormal uptake was observed they received the planned dose. On Day −7 and 0 imaging and therapeutic doses were preceded by rituximab 250mg/mq. On Day13 pts were reinfused with PBSC previously harvested. On Day28 from reinfusion engraftment was considered to be delayed if WBC/ANC were<1.0x109/L or PLT<20x109/L. All pts engrafted promptly after PBSCT with median time to WBC/ANC>1.0x109/L and PLT>20x109/L of 19 (range 0–23) and 12 days (0–22) from PBSCT. PLT and ANC count nadirs were observed at 21 (0–24) and 25 (0–31) days after Zevalin with median values of 11x109/L(4–35) and 0.24x109/L(0.01–1.09). Median time to recovery from nadir was 16,5 days (4–175) for PLT and 17days (7–175) for ANC. 8pts required PLT transfusions, 4pts RBC transfusions; median number of PLT transfusions:1(1–4). No G-CSF was administered. No significant differences in terms of haematologic toxicity were observed among the 3 levels. No pulmonary, renal or cardiac toxicity was observed. 11/12 pts are now evaluable for response: 5pts experienced a CR (2 at 0.8mCi/kg, 2 at 1.2mCi/kg, 1 at 1.5mCi/kg), 1 pt receiving 1.5 mCi/kg a PR (ORR 50%); to date 4 pts maintain CR at 12, 11, 9 and 8 months after treatment. Conclusion: Zevalin at dosage higher than MTD is feasible with PBSC support. Even at dosage 4 times higher than standard, HD-Zevalin could be safely delivered in elderly and heavily pretreated pts, including those who previously received HD-CT. Clinical activity and mild treatment-related toxicities suggest that HD-Zevalin is an interesting modality treatment to be further investigated as an alternative therapeutic options for resistant-refractory NHL.

Phase I Study of IMGN901 in Patients with Relapsed and Relapsed/Refractory CD56-Positive Multiple Myeloma

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3689-3689 ◽  
Author(s):  
Asher Alban Chanan-Khan ◽  
Mecide Gharibo ◽  
Sundar Jagannath ◽  
Nikhil C. Munshi ◽  
Kenneth C Anderson ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Phase I ◽  
Phase I Study ◽  
Maximum Tolerated Dose ◽  
Preliminary Evidence ◽  
Clinical Activity ◽  
Weekly Schedule ◽  
Minor Response

Abstract Background: IMGN901 (huN901-DM1) is a novel conjugate of the cytotoxic maytansinoid, DM1, with the humanized CD56-binding monoclonal antibody, N901. Once bound to CD56 on a cancer cell, the conjugate is internalized and releases DM1. About 70% of multiple myeloma (MM) cases have surface expression of CD56. Preclinical investigations demonstrated significant in vitro and in vivo anti-myeloma activity of IMGN901. Objectives: To determine the maximum tolerated dose (MTD), the dose-limiting toxicities (DLTs), and pharmacokinetics (PK) of increasing doses of IMGN901 given for MM on a weekly schedule. Methods: Patients with relapsed or relapsed/refractory MM who have failed at least one prior therapy and have CD56-expressing MM received a single IV infusion of IMGN901 on 2 consecutive weeks every 3 weeks. Patients are enrolled in cohorts of 3 at each dose level, with DLT triggering cohort expansion. Results: Eighteen patients have received IMGN901 to date in this study - 3 patients each at 40, 60, 75, 90, 112, and 140 mg/m2/week. One patient experienced a DLT (grade 3 fatigue) on 140 mg/m2/week, and this cohort is being expanded to enroll up to 6 patients. No patients have experienced serious hypersensitivity reactions or evidence of presence of humoral responses against the huN901 antibody component (HAHA) or against the DM1 component (HADA). Preliminary PK results indicate an approximately linear relationship between dosing and observed maximal serum concentration. A confirmed minor response (MR) was documented in 3 heavily pretreated patients (1 patient each at 60, 90, and 112 mg/m2/week) using the European Bone Marrow Transplant criteria. Durable stable disease was reported at doses of 60, 90, 112, and 140 mg/m2/week. Of the 18 patients treated in the study, eight patients remained on treatment with IMGN901 for at least 15 weeks, five of these 8 patients remained on treatment for at least 24 weeks, and two of these 5 patients remained on treatment for at least 42 weeks. This phase I study provides preliminary evidence of safety as well as clinical activity of IMGN901 in patients with CD56-positive MM who have failed established MM treatments. Updated results of this ongoing study will be presented.

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