Phase 1/2 Trial of Durvalumab and Lenalidomide in Patients with Cutaneous T Cell Lymphoma (CTCL): Preliminary Results of Phase I Results and Correlative Studies

Abstract Background: In CTCL, intratumoral T cells are functionally exhausted and are characterized by the expression of immune inhibitory molecules such as PD1 and PD-L1 (Cancer Immunol Res 6; 2018). These findings justify the evaluation of immune checkpoint inhibition to reverse T cell exhaustion in CTCL. To this end, we initiated a phase 1/2 clinical trial of lenalidomide and durvalumab to determine the safety and efficacy of this regimen. Durvalumab is a human monoclonal antibody with high affinity and selectivity for PD-L1, with mechanisms of action that target the exhausted T cells and distinct cells within their environment. Lenalidomide, an oral immunomodulatory drug and analog of thalidomide, has previously shown activity in CTCL (Blood 123; 2014). Durvalumab may restore an anti-tumor immune response, and the combination of durvalumab and lenalidomide may enhance immune checkpoint blockade-induced immune responses. Methods: A Phase 1 portion is ongoing to characterize the safety and tolerability of durvalumab and lenalidomide combination. Patients (pts) are enrolled in sequential cohorts to receive durvalumab (fixed dose at 1500 mg) and dose escalation of lenalidomide (cohort 1 = 10 mg; cohort 2 = 15 mg; subsequent planned dose increments of 5 mg) to evaluate safety, efficacy and antitumor activity. Serial skin and blood samples were collected to assess the impact on the tumor micro-environment. We examined the correlation between clinical response and resistance and the following biological factors: PD1 clustering at the single molecule level using super-resolution microscopy, and expression of PD-L1 and ICOS at the tissue level by means of multiplex immunohistochemistry on pre-treatment primary cells (migrated from skin explants), and skin tissue (formalin-fixed and paraffin-embedded) from clinical trial subjects. Results: Six patients (5 males/1female, age 32-57 years) with refractory/advanced CTCL (mycosis fungoides/Sezary syndrome subtype), clinical stage IB (1), IIA (1), IIB (3), IIIA (1) have been enrolled as of July 2018. Duration time on treatment was 4 to 13+ months. Four patients showed improvement of skin disease with 2 patients achieved partial response with > 90% improvement of skin disease by mSWAT. Two patients developed progressive disease. No serious adverse events (AEs) were observed. The most frequently reported AEs were fatigue (n=6), skin pain (n=4), anemia (n=3) chills (n=4), and decreased appetite (n=3). All treatment-related AEs were Grade 1 or 2 in severity. One grade 3 fatigue occurred in one patient. No dose limiting toxicity has been observed to date. Using multispectral microscopy, we analyzed expression panels of several checkpoints: PD1, PD-L1, and ICOS on lesional skin biopsies at baseline. Strong PD-L1 and ICOS expression is observed from non-responders. Detectable levels of PD-L1, but low levels of ICOS is observed in responding patients. Quantitative super-resolution microscopy detected nanoscale clusters of PD1 in T cells from responders and no PD1 clustering was observed in T cells from non-responders. Conclusions: Durvalumab/lenalidomide has significant clinical activity in patients with refractory/advanced CTCL, which will be formally evaluated in the Phase 2 portion of this trial. Responses were durable and ongoing, and treatment was well tolerated with a low toxicity profile. Dose escalation is planned up to lenalidomide 20 mg daily. Our preliminary results from patients on trial demonstrated that immune signatures on skin biopsies at baseline may be predictive of response to checkpoint blockade and yield insights into mechanisms of therapeutic resistance. Disclosures Querfeld: Acelion: Membership on an entity's Board of Directors or advisory committees; Kyowa: Membership on an entity's Board of Directors or advisory committees; Bioniz: Membership on an entity's Board of Directors or advisory committees; Medivir: Membership on an entity's Board of Directors or advisory committees; Trillium Therapeutics: Membership on an entity's Board of Directors or advisory committees.

Download Full-text

Preliminary Clinical Results from a Phase 1 Study of ACTR707 in Combination with Rituximab in Subjects with Relapsed or Refractory CD20+ non-Hodgkin Lymphoma

Blood ◽

10.1182/blood-2019-125995 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1587-1587

Author(s):

Ian W. Flinn ◽

Jason R. Westin ◽

Jonathon B. Cohen ◽

Luke P. Akard ◽

Samantha Jaglowski ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Board Of Directors ◽

Dose Escalation ◽

Research Funding ◽

Phase 1 ◽

Advisory Board ◽

Phase 1 Study ◽

Advisory Committees ◽

Clinical Responses

Background: The Antibody-Coupled T-cell Receptor (ACTR) platform is an autologous engineered T-cell therapy that combines the cell-killing ability of T cells and the tumor-targeting ability of co-administered antibodies to exert potent antitumor immune responses. ACTR707 comprises the extracellular domain of CD16 linked to a CD3ζ signaling domain and a CD28 co-stimulatory domain. ACTR707 is in clinical development in combination with rituximab (NCT03189836) or trastuzumab (NCT03680560). Here we present clinical findings from the dose escalation phase of Study ATTCK-20-03, an ongoing, multicenter, phase 1 study of ACTR707+rituximab in subjects with relapsed or refractory (R/R) CD20+ NHL. Methods: The primary objectives of this first-in-human study are to evaluate the safety of the combination of ACTR707 and rituximab and to determine a recommended phase 2 dose (RP2D). Other objectives include evaluating antitumor activity and ACTR T-cell persistence. Subjects must have CD20+ NHL that is R/R after prior treatments, which must include anti-CD20 antibody-containing chemotherapy. Subjects receive lymphodepleting chemotherapy (cyclophosphamide and fludarabine) for 3 days, followed by rituximab and a single dose of ACTR707. Additional doses of rituximab are administered q3w until disease progression, unacceptable toxicity, or Investigator decision. The study includes a dose escalation phase (increasing doses of ACTR707 with fixed dose of rituximab at 375 mg/m2 q3w) and an expansion phase at the RP2D. Results: Six subjects received ACTR707 at Dose Level 1 (DL1; 23-38×106 ACTR+ T cells), 3 subjects at DL2 (30-50×106 ACTR+ T cells), and 5 subjects at DL3 (45-55×106 ACTR+ T cells). The majority of the subjects were diagnosed with DLBCL (93%) and had refractory disease (71%), defined as progressive disease as the best response to any prior treatment or relapse <1 year post autologous stem cell transplant. In DL1 through DL3, as of 27 May 2019, there were no dose-limiting toxicities, AEs of cytokine release syndrome (CRS), serious or severe neurologic AEs, or AEs leading to deaths on treatment. TEAEs reported in >2 subjects, regardless of causality or grade, included neutropenia, thrombocytopenia, anemia, febrile neutropenia, pyrexia, cough, constipation, diarrhea, nausea, and vomiting. SAEs considered possibly related to ACTR707 were febrile neutropenia (n=2) and cytopenia (n=1). ACTR707 expansion generally reached peak levels within 1 to 2 weeks after administration. All subjects with complete response (CR) up to 1 year had detectable ACTR at the last timepoint evaluated. Higher ACTR707 CD8:CD4 T-cell ratios were associated with clinical responses. Clinical activity was reported across DL1 through DL3, with an overall response rate of 64% including durable complete responses (CRs), with one subject in CR for 387+ days (Table 1). Conclusions: Data available from DL1 through DL3 of ACTR707+rituximab suggest that clinical responses can be achieved without severe T cell-mediated toxicities (eg, CRS and neurotoxicity) that have been reported with other autologous T-cell products. Dose escalation continues at a target dose of 80×106 ACTR+ T cells; enrollment in DL4 (n=6) was recently completed. Updated data, including identified correlates of clinical outcomes, will be presented for DL1 through DL4. Disclosures Flinn: TG Therapeutics, Trillum Therapeutics, Abbvie, ArQule, BeiGene, Curis, FORMA Therapeutics, Forty Seven, Merck, Pfizer, Takeda, Teva, Verastem, Gilead Sciences, Astra Zeneca (AZ), Juno Therapeutics, UnumTherapeutics, MorphoSys, AG: Research Funding; AbbVie, Seattle Genetics, TG Therapeutics, Verastem: Consultancy; TG Therapeutics, Trillum Therapeutics, Abbvie, ArQule, BeiGene, Curis, FORMA Therapeutics, Forty Seven, Merck, Pfizer, Takeda, Teva, Verastem, Gilead Sciences, Astra Zeneca (AZ), Juno Therapeutics, UnumTherapeutics, MorphoSys, AG: Research Funding; Acerta Pharma, Agios, Calithera Biosciences, Celgene, Constellation Pharmaceuticals, Genentech, Gilead Sciences, Incyte, Infinity Pharmaceuticals, Janssen, Karyopharm Therapeutics, Kite Pharma, Novartis, Pharmacyclics, Portola Pharmaceuticals: Research Funding; F. Hoffmann-La Roche Ltd: Research Funding. Westin:Genentech: Other: Advisory Board, Research Funding; Janssen: Other: Advisory Board, Research Funding; Kite: Other: Advisory Board, Research Funding; Unum: Research Funding; Curis: Other: Advisory Board, Research Funding; Juno: Other: Advisory Board; MorphoSys: Other: Advisory Board; 47 Inc: Research Funding; Celgene: Other: Advisory Board, Research Funding; Novartis: Other: Advisory Board, Research Funding. Cohen:Genentech, Inc.: Consultancy, Research Funding; Takeda Pharmaceuticals North America, Inc.: Research Funding; Gilead/Kite: Consultancy; LAM Therapeutics: Research Funding; UNUM: Research Funding; Hutchison: Research Funding; Astra Zeneca: Research Funding; Lymphoma Research Foundation: Research Funding; ASH: Research Funding; Bristol-Meyers Squibb Company: Research Funding; Seattle Genetics, Inc.: Consultancy, Research Funding; Janssen Pharmaceuticals: Consultancy. Akard:Celgene: Speakers Bureau; Novartis: Speakers Bureau; Takeda: Speakers Bureau; Bristol-Myers Squibb: Speakers Bureau; Gilead: Speakers Bureau. Jaglowski:Juno: Consultancy, Other: advisory board; Kite: Consultancy, Other: advisory board, Research Funding; Unum Therapeutics Inc.: Research Funding; Novartis: Consultancy, Other: advisory board, Research Funding. Sachs:Unum Therapeutics Inc.: Employment. Ranger:Unum Therapeutics Inc.: Employment. Harris:Unum Therapeutics Inc.: Employment. Payumo:Unum Therapeutics Inc.: Employment. Bachanova:Celgene: Research Funding; Gamida Cell: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; GT Biopharma: Research Funding; Kite: Membership on an entity's Board of Directors or advisory committees; Incyte: Research Funding; Novartis: Research Funding.

Download Full-text

Safety Data from a First-in-Human Phase 1 Trial of NKG2D Chimeric Antigen Receptor-T Cells in AML/MDS and Multiple Myeloma

Blood ◽

10.1182/blood.v128.22.4052.4052 ◽

2016 ◽

Vol 128 (22) ◽

pp. 4052-4052 ◽

Cited By ~ 16

Author(s):

Sarah Nikiforow ◽

Lillian Werner ◽

Joana Murad ◽

Matthew Jacobs ◽

Lauren Johnston ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Board Of Directors ◽

Dose Escalation ◽

Phase 1 ◽

Hematologic Malignancies ◽

Advisory Committees ◽

Cd8 Cells ◽

Car T Cells ◽

Car T

Abstract Introduction: Conventional CAR-T cells express a single chain antibody variable fragment that restricts recognition to one tumor antigen and a limited set of cancers. This study employs a novel CAR fusing full-length human NKG2D with the CD3z signaling domain. In autologous transduced CM-CS1 T cells, NKG2D CAR receives endogenous costimulation via DAP10 to target multiple NKG2D-ligands that are upregulated in solid and hematologic malignancies but absent or poorly expressed on healthy tissues. Methods: A phase 1 dose-escalation study to establish safety and feasibility of a single infusion of CM-CS1 T cells without lymphodepleting conditioning enrolled subjects with AML/MDS-RAEB or relapsed/refractory progressive multiple myeloma (MM) without standard therapy options (NCT02203825). Eligibility criteria included suitable organ function, no CNS disease, no prior allogeneic SCT or adoptive T-cell therapy, no therapy within 3 weeks prior to infusion, no immune suppression, and no uncontrolled infection. Dose-escalation spanned 4 cohorts [half-log increments from 1x106 to 3x107 CM-CS1 T cells] according to a 3+3 design. DLTs included ≥ Grade 3 non-hematologic toxicity or ≥ Grade 2 autoimmune toxicity related to CAR T cells. Initial assessment was at 28 days. At least 1 AML/MDS and 1 MM subject were mandated in each dose level. Manufacturing included PBMC stimulation with OKT3 and IL-2 followed by 2 rounds of retroviral transduction at DFCI's Cell Manipulation Core Facility. Vector copy number (VCN) and replication-competent retrovirus (RCR) testing were performed on whole blood and PBMCs, respectively, using quantitative PCR. Results: From April 2015 to July 2016, 11 subjects were infused, and 10 completed the DLT period. Eight of 11 were male, 6 had AML/MDS, and median age was 70 (range 44 to 79) (Panel A). Median WBC was 2.3 (range 0.7 to 7.2 K/uL); median ALC was 0.74 (range 0.09-2.37 K/uL). Five had cells manufactured from peripheral blood; 6 underwent apheresis. Median percentage of blasts in bone marrow for AML/MDS patients was 50% (range 4-68%). All myeloma patients had undergone ≥ 5 therapies including ≥1 autologous SCT. Four of the 6 AML/MDS patients had secondary disease, 3 had complex cytogenetics, 3 had p53 mutations, and 1 had a FLT3-ITD mutation. Dose-escalation proceeded from 1x106 to 3x107 CM-CS1 T cells. All 11 products passed release criteria, and there were no infusion reactions. Products consisted of median 97.2% CD3+ cells and 31.0% CD8+ cells, with vector-specific NKG2D expression on median 74.6% of CD3+ and 66.3% of CD8+ cells (Panel B). The first 10 subjects completed their 28 day evaluation period without DLTs. There were no cases of cytokine release syndrome, cell-related neurotoxicity, auto-immunity, or CAR T-related death. SAEs included a Grade 4 intracochlear bleed and an episode each of grade 4 neutropenia and thrombocytopenia deemed related to disease progression. Forty percent of patients experienced some Grade 3 toxicity, all related to underlying disease or a complication thereof (Panel C). At these initial cell doses, no patient to date has had objective tumor response at the 28 day evaluation mark. Nine initiated subsequent therapies; there have been 4 deaths secondary to disease or complications of subsequent therapies. However, cases of unexpected survival without further therapy and responses to subsequent treatments were noted. For example a patient with p53-mutated AML survived 4 months despite 50% blasts at infusion, and another entered PR at 6+months after cells on an IDH-1 inhibitor with <5% IDH and 54% p53 mutation burden at initiation. RCR testing at 3 (n=6) and 6 months (n=1) was negative. As anticipated, no CAR T cell persistence has been detected at or beyond 2 weeks, with 1 exception. CAR T cell DNA has been detected sporadically from 1 hour to 1 week after infusion. Conclusion: In the first 3+ dose-escalation cohorts of patients with AML/MDS and myeloma, a single dose of CM-CS1 T cells without lymphodepletion was feasible and well-tolerated, with no DLTs. CAR T cells generally have not persisted beyond 1 week, consistent with pre-clinical models. Correlative analyses including post-infusion immunophenotyping are in process. Future studies of multiple infusions of NKG2D CAR T cells in both hematologic malignancies and solid tumors at the higher cell doses associated with efficacy in pre-clinical models are in planning. Table Table. Disclosures Murad: Celdara Medical, LLC: Employment. Reder:Celdara Medical, LLC: Employment. Sentman:Celdara Medical, LLC: Membership on an entity's Board of Directors or advisory committees, Other: Holds patents on this technology. Wade:Celdara Medical, LLC: Employment. Schmucker:Celdara Medical, LLC: Employment. Lehmann:Celyad, SA: Employment. Snykers:Celyad, SA: Employment. Allen:Celyad, SA: Employment. Stone:Celator: Consultancy; Jansen: Consultancy; Novartis: Consultancy; Merck: Consultancy; ONO: Consultancy; Sunesis Pharmaceuticals: Consultancy; Roche: Consultancy; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Juno Therapeutics: Consultancy; Xenetic Biosciences: Consultancy; Agios: Consultancy; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy; Pfizer: Consultancy; Karyopharm: Consultancy; Amgen: Consultancy. Soiffer:Kiadis: Membership on an entity's Board of Directors or advisory committees; Juno: Consultancy. Dranoff:Novartis: Employment. Ritz:Kiadis: Membership on an entity's Board of Directors or advisory committees.

Download Full-text

Final Results of Phase 1/1b Study of Tenalisib, Dual PI3K δ/γ Inhibitor in Patients with Relapsed/Refractory T-Cell Lymphoma

Blood ◽

10.1182/blood-2019-123954 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 2831-2831 ◽

Cited By ~ 1

Author(s):

Swaminathan P. Iyer ◽

Brad M. Haverkos ◽

Jasmine Zain ◽

Radhakrishnan Ramchandren ◽

Mary Jo Lechowicz ◽

...

Keyword(s):

T Cell ◽

Adverse Events ◽

Board Of Directors ◽

Dose Escalation ◽

Safety Profile ◽

Research Funding ◽

Cell Lymphoma ◽

Phase 1 ◽

Clinical Activity ◽

Advisory Committees

Introduction: Tenalisib (RP6530) is a novel, highly specific, dual PI3K δ/γ inhibitor with nano-molar inhibitory potency at the enzyme and cellular level. PI3K plays a critical role in T-cell development and activation and several studies have validated the PI3K-AKT pathway as a potential therapeutic target in T cell lymphomas. Preliminary results of the ongoing Phase 1/1b T-cell lymphoma (TCL) study demonstrated an acceptable safety profile with encouraging clinical activity in relapsed/refractory TCL (Oki, ASCO 2018 and Iyer, ASH 2018). We now present the final results of the study (NCT02567656). Methods: This study comprised of four-dose escalation cohorts, followed by two dose expansion cohorts at MTD enrolling 20 patients each in PTCL and CTCL cohorts. Patients had histologically confirmed TCL, ECOG PS ≤2, and had received ≥1 prior therapy. Patients received Tenalisib [200 mg BID-800 mg BID (fasting), 800 mg (fed only)] orally until progression or unacceptable toxicity. The primary objectives were to determine the MTD and pharmacokinetic profile. The secondary objective was to evaluate overall response rate (ORR) and duration of response. Responses were evaluated for PTCL and CTCL based on IWG criteria (Cheson 2007) and mSWAT respectively. Adverse events were graded according to CTCAE v4.03. Results: Fifty-eight patients were enrolled in study, 19 in dose escalation and 39 in dose expansion (28 PTCL and 30 CTCL). Median number of prior therapies was 4 (range, 1-15). Safety assessment of 58 patients receiving at least one dose of Tenalisib demonstrated an acceptable safety profile. Treatment related Grade≥3 AEs were elevated ALT/AST (21%), rash (5%), and hypophosphatemia (3%). These events were reversible and managed by withholding study drug. Additionally, in few patients (N=9), steroids were used to manage elevated ALT/AST. There were six treatment related serious adverse events, none of these led to fatal outcome. At end of the study, four (3 CTCL; 1 PTCL) patients who completed minimum 8 cycles of therapy were rolled over to a compassionate use study (NCT03711604) and were followed up. Efficacy assessments demonstrated an ORR of 46% (3 CR and 13 PR) and clinical benefit rate (CR+PR+SD) of 77%. Subset efficacy analysis showed an ORR in PTCL of 47% (3 CR; 4 PR) and in CTCL of 45% (9 PR). The median time to initial response was 1.8 months and was similar in both sub-types. The overall median DOR was 4.91 months (range 0.9-26.6); in PTCL patients the DOR was 6.53 months, (range: 0.97-21.0) and 3.8 months (range: 1.67-25.67) in CTCL patients. In 3 PTCL patients who achieved CR, the median DOR was 19.5 months (range 7.5-21). Conclusion: Tenalisib demonstrated promising clinical activity and an improved safety profile in patients with relapsed/ refractory TCL. Currently, a phase I/II combination study to further evaluate safety and efficacy with romidepsin is ongoing in this target population. Disclosures Iyer: Arog: Research Funding; Bristol-Myers Squibb: Research Funding; Novartis: Research Funding; Seattle Genetics, Inc.: Research Funding; Genentech/Roche: Research Funding; Incyte: Research Funding. Zain:Spectrum: Consultancy; Seattle Genetics: Consultancy. Korman:Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Glaxo: Honoraria, Membership on an entity's Board of Directors or advisory committees; Immune Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Kyowa: Research Funding; Leo: Research Funding; Menlo: Research Funding; Merck: Research Funding; Novartis: Consultancy, Honoraria, Speakers Bureau; Pfizer: Research Funding; Principia: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Prothena: Research Funding; Regeneron: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Rhizen: Research Funding; Sun: Honoraria, Membership on an entity's Board of Directors or advisory committees; Syntimmune: Research Funding; UCB: Research Funding; Valeant: Honoraria, Membership on an entity's Board of Directors or advisory committees; Eli Lilly: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Dermira: Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Research Funding; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Routhu:Rhizen Pharmaceuticals S.A.: Employment. Barde:Rhizen Pharmaceuticals S.A.: Employment. Nair:Rhizen Pharmaceuticals S.A.: Employment. Huen:Galderma Inc: Research Funding; Glaxo Smith Kline Inc: Research Funding; Rhizen Pharmaceuticals: Research Funding; Innate Pharmaceuticals: Research Funding.

Download Full-text

A Phase 1 Study of Sea-CD70 in Myeloid Malignancies

Blood ◽

10.1182/blood-2020-136203 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 23-24

Author(s):

Ahmed Aribi ◽

Anjali S Advani ◽

William Donnellan ◽

Amir T. Fathi ◽

Marcello Rotta ◽

...

Keyword(s):

Board Of Directors ◽

Immune Evasion ◽

Dose Escalation ◽

Research Funding ◽

Phase 1 ◽

Steering Committee ◽

Advisory Board ◽

Open Label ◽

Advisory Committees ◽

Myeloid Malignancies

Background SEA-CD70 is being developed in myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). Current treatment options are limited for patients (pts) with relapsed or refractory (r/r) MDS or r/r AML and outcomes remain poor. SEA-CD70 is an investigational humanized, non-fucosylated monoclonal antibody targeting CD70. Expression of CD70 is limited in normal tissue, but is aberrantly expressed on malignant myeloid blasts while absent from healthy hematopoietic progenitor cells. CD70 and its ligand, CD27, may play a role in malignant blast cell survival and/or tumor immune evasion. SEA-CD70 uses a novel sugar-engineered antibody (SEA) platform to produce a non-fucosylated antibody with enhanced effector function. The proposed mechanism of action of SEA-CD70 includes elimination of CD70 positive cells via enhanced antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), and mediation of complement-dependent cytoxicity (CDC). Additionally, SEA-CD70 has the potential to block the interaction of CD70 with CD27, which may disrupt signals that enhance blast proliferation and survival and may modulate the immune system to limit immune evasion and increase antigen specific T cell responses. Methods SGNS70-101 is a phase 1, open-label, multicenter, dose-escalation, and cohort expansion study designed to establish the safety, tolerability, and preliminary activity of SEA-CD70 in pts with myeloid malignancies (NCT04227847). Dose escalation is ongoing. In dose escalation, pts must have r/r MDS with 5-20% blasts which has failed prior treatment with a hypomethylating agent (HMA), and have no other therapeutic options known to provide clinical benefit for MDS. After conclusion of dose escalation, monotherapy expansion cohorts will be opened for pts with MDS and for pts with AML. Primary objectives are to evaluate the safety and tolerability, and to determine the maximum tolerated dose (MTD) or recommended expansion dose of SEA-CD70. Secondary objectives are to assess antitumor activity, PK, and immunogenicity of SEA-CD70. Once dose escalation is complete and the recommended monotherapy dose is identified, combination cohorts will be considered in AML and MDS. The study is currently enrolling with sites opening in the US and EU. Disclosures Aribi: Seattle Genetics: Consultancy. Advani:OBI: Research Funding; Takeda: Research Funding; Novartis: Consultancy, Other: advisory board; Pfizer: Honoraria, Research Funding; Kite: Other: Advisory board/ honoraria; Amgen: Consultancy, Other: steering committee/ honoraria, Research Funding; Seattle Genetics: Other: Advisory board/ honoraria, Research Funding; Immunogen: Research Funding; Glycomimetics: Consultancy, Other: Steering committee/ honoraria, Research Funding; Macrogenics: Research Funding; Abbvie: Research Funding. Donnellan:Kite Pharma/Gilead: Research Funding; Janssen: Research Funding; Karyopharm Therapeutics: Research Funding; AstraZeneca: Research Funding; Astex Pharmaceuticals: Research Funding; Incyte: Research Funding; MedImmune: Research Funding; TCR2 Therapeutics: Research Funding; Genentech: Research Funding; PTC Therapeutics: Consultancy, Research Funding; Pfizer: Research Funding; Daiichi Sankyo: Research Funding; Bristol-Myers Squibb: Research Funding; Amgen: Consultancy; Abbvie: Consultancy, Research Funding; Bellicum Pharmaceuticals: Research Funding; CTI Biopharma: Research Funding; Celgene: Research Funding; Celularity: Research Funding; Forma Therapeutics: Research Funding; Forty Seven: Research Funding; Takeda: Research Funding; H3 Biomedicine: Research Funding; Ryvu Therapeutics: Research Funding; Seattle Genetics: Consultancy, Research Funding. Fathi:Astellas: Consultancy; Agios: Consultancy, Research Funding; Amphivena: Consultancy, Honoraria; AbbVie: Consultancy; Pfizer: Consultancy; Daiichi Sankyo: Consultancy; Celgene: Consultancy, Research Funding; Forty Seven: Consultancy; Jazz: Consultancy, Honoraria; Kite: Consultancy, Honoraria; NewLink Genetics: Consultancy, Honoraria; Novartis: Consultancy; PTC Therapeutics: Consultancy; Takeda: Consultancy; TrovaGene: Consultancy; Amgen: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Blue Print Oncology: Consultancy; Boston Biomedical: Consultancy; Kura: Consultancy; Trillium: Consultancy; Seattle Genetics: Consultancy, Research Funding. Rotta:Merck: Speakers Bureau; Jazz Pharma: Speakers Bureau. Vachani:Blueprint: Consultancy; CTI Biopharma: Consultancy; Daiichi Sankyo: Consultancy; Incyte: Consultancy, Research Funding; Jazz: Consultancy; Astellas: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy; Abbvie: Consultancy. Yang:AROG: Research Funding; Protagonist: Research Funding; Jannsen: Research Funding; AstraZeneca: Research Funding. Ho:Seattle Genetics: Current Employment, Current equity holder in publicly-traded company. Garcia-Manero:Novartis: Research Funding; Helsinn Therapeutics: Consultancy, Honoraria, Research Funding; Merck: Research Funding; Jazz Pharmaceuticals: Consultancy; Onconova: Research Funding; Amphivena Therapeutics: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Acceleron Pharmaceuticals: Consultancy, Honoraria; AbbVie: Honoraria, Research Funding; Astex Pharmaceuticals: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; H3 Biomedicine: Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Download Full-text

A Phase 1/2 Study of the Second Generation Selective Inhibitor of Nuclear Export (SINE) Compound, KPT-8602, in Patients with Relapsed Refractory Multiple Myeloma

Blood ◽

10.1182/blood.v128.22.4509.4509 ◽

2016 ◽

Vol 128 (22) ◽

pp. 4509-4509 ◽

Cited By ~ 4

Author(s):

R. Frank Cornell ◽

Adriana C Rossi ◽

Rachid Baz ◽

Craig C Hofmeister ◽

Chaim Shustik ◽

...

Keyword(s):

Clinical Trial ◽

Board Of Directors ◽

Nuclear Export ◽

Research Funding ◽

Low Dose ◽

Phase 1 ◽

Single Agent ◽

Employment Equity ◽

Advisory Committees ◽

Equity Ownership

Abstract Introduction - Inhibition of Exportin 1 (XPO1) is a novel treatment approach for multiple myeloma (MM). XPO1 mediates the nuclear export of cell-cycle regulators and tumor suppressor proteins leading to their functional inactivation. In addition, XPO1 promotes the export and translation of the mRNA of key oncoproteins (e.g. c-MYC, BCL-2, Cyclin D). XPO1 overexpression occurs in solid and hematological malignancies, including MM and is essential for MM cell survival. Selinexor, the first oral SINE compound, has shown promising anti-MM activity in phase 1 studies but has been associated with gastrointestinal and constitutional toxicities including nausea, anorexia and fatigue. KPT-8602 is a second generation oral SINE compound with similar in vitro potency to selinexor, however, has substantially reduced brain penetration compared with selinexor, and demonstrated markedly improved tolerability with minimal anorexia and weight loss in preclinical toxicology studies. In murine models of MM, KPT-8602 can be dosed daily (QDx5) with minimal anorexia and weight loss. We have therefore initiated a phase 1/2 first-in-human clinical trial. Methods - This phase 1/2 clinical trial was designed to evaluate KPT-8602 as a single agent and in combination with low dose dexamethasone (dex) in patients (pts) with relapsed / refractory MM (RRMM). KPT-8602 is dosed orally (QDx5) for a 28-day cycle with a starting dose of 5 mg. Low dose dex (20 mg, twice weekly) is allowed after cycle 1 if at least a minimal response (MR) is not observed. The primary objective is to evaluate the safety and tolerability including dose-limiting toxicity (DLT), determine the maximum tolerated dose (MTD), the recommended Phase 2 dose (RP2D), and evidence for anti-MM activity for KPT-8602 single agent and in combination with dex. The pharmacokinetic (PK) and pharmacodynamic (PDn; XPO1 mRNA) profile of KPT-8602 will also be determined. PDn predictive biomarker analysis and ex vivo drug response assays are underway using tumor cells from bone marrow aspirates before treatment, during and at relapse. These analyses include cell death pathway assays by flow and nuclear/cytoplasmic localization of XPO1, NF-ƙB, IƙBα, IKKα, NRIF and p53 by imaging flow and IHC. Results - As of 01-Aug-2016, 6 pts 2 M/4 F, (median of 6 prior treatment regimens, median age of 71) with RRMM have been enrolled. Common related grade 1/2 adverse events (AEs) include thrombocytopenia (3 pts), nausea (2 pts) and diarrhea (2 pts). Grade 3 AEs include neutropenia (1 pt) and dehydration (1 pt). No grade 4 or 5 AEs have been reported. No DLTs have been observed and the MTD has not been reached. 5 pts were evaluable for responses (1 pt pending evaluation): 1 partial response, 1 minimal response, and 3 stable disease; no pts have progressed on therapy with the longest on for >5 months. The PK properties following oral administration showed that 5 mg of KPT-8602 was rapidly absorbed (mean tmax= 1 hr, mean Cmax= 30.6 ng/mL). The mean AUCinf was calculated to be 141 ng•hr/mL. After tmax, KPT-8602 declined at an estimated mean t½ of 4 hr. At the same dose level, XPO1 mRNA expression was the highest (~2.5 fold) at 8 hr post dose. Conclusions - Oral KPT-8602 is well tolerated in heavily pretreated pts with RRMM. Gastrointestinal and constitutional toxicities observed with twice weekly selinexor have not been observed with 5x/week KPT-8602, including in pts on study for >4 months. PK was predictable and in line with selinexor. These early results show encouraging disease control with pts remaining on therapy. Enrollment is on-going. Disclosures Rossi: Takeda: Speakers Bureau; Janssen: Speakers Bureau; Onyx: Research Funding, Speakers Bureau; Celgene: Consultancy, Speakers Bureau. Baz:Takeda/Millennium: Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Research Funding; Signal Genetics: Research Funding; Bristol-Myers Squibb: Research Funding; Merck: Research Funding; Novartis: Research Funding. Hofmeister:Karyopharm Therapeutics: Research Funding; Arno Therapeutics, Inc.: Research Funding; Signal Genetics, Inc.: Membership on an entity's Board of Directors or advisory committees; Janssen: Pharmaceutical Companies of Johnson & Johnson: Research Funding; Incyte, Corp: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Takeda Pharmaceutical Company: Research Funding; Teva: Membership on an entity's Board of Directors or advisory committees. Shustik:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Millenium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Richter:Amgen: Consultancy, Speakers Bureau; Takeda: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Jannsen: Speakers Bureau. Chen:Janssen: Honoraria, Research Funding; Takeda: Research Funding; Celgene: Honoraria, Research Funding. Vogl:Takeda: Consultancy, Research Funding; Celgene: Consultancy; GSK: Research Funding; Calithera: Research Funding; Teva: Consultancy; Karyopharm: Consultancy; Acetylon: Research Funding; Constellation: Research Funding. Shacham:Karyopharm Therapeutics: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Baloglu:Karyopharm Therapeutics: Employment, Equity Ownership. Senapedis:Karyopharm Therapeutics: Employment, Equity Ownership. Ellis:Karyopharm Therapeutics: Employment, Equity Ownership. Friedlander:Karyopharm Therapeutics: Employment. Choe-Juliak:Karyopharm Therapeutics: Employment. Sullivan:Karyopharm Therapeutics: Research Funding. Kauffman:Karyopharm Therapeutics Inc: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees.

Download Full-text

Phase I/II dose escalation and expansion study of FLX475 alone and in combination with pembrolizumab in advanced cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.8_suppl.tps24 ◽

2019 ◽

Vol 37 (8_suppl) ◽

pp. TPS24-TPS24

Author(s):

William Ho ◽

Nicole Nasrah ◽

Dan Johnson

Keyword(s):

Clinical Trial ◽

T Cells ◽

Dose Escalation ◽

Checkpoint Inhibitors ◽

Phase 1 ◽

Single Agent ◽

Safety Data ◽

Receptor Occupancy ◽

Open Label ◽

Ligand Expression

TPS24 Background: Regulatory T cells (Treg) can dampen anti-tumor immune responses in the tumor microenvironment (TME). The predominant chemokine receptor on human Treg is CCR4, the receptor for the chemokines CCL17 and CCL22, which are produced by tumor cells, tumor-associated macrophages and dendritic cells, as well as by effector T cells (Teff) in the setting of an inflammatory anti-tumor response. Preclinical studies with orally-available CCR4 antagonists have demonstrated potent inhibition of Treg migration into tumors, an increase in the intratumoral Teff/Treg ratio, and anti-tumor efficacy as a single agent and in combination with checkpoint inhibitors. In a first-in-human trial conducted in healthy volunteers, the oral CCR4 antagonist FLX475 was demonstrated to be well tolerated with outstanding PK properties. A robust PD assay measuring receptor occupancy on circulating Treg demonstrated the ability to safely achieve exposure levels predicted to maximally inhibit Treg recruitment into tumors via CCR4 signaling. These human PK, PD, and safety data have enabled a streamlined design of a Phase 1/2 study of FLX475 in cancer patients both as monotherapy and in combination with checkpoint inhibitor. Methods: This clinical trial is a Phase 1/2, open-label, dose-escalation and cohort expansion study to determine the safety and preliminary anti-tumor activity of FLX475 as monotherapy and in combination with pembrolizumab. The study is being conducted in 2 parts, a dose-escalation phase (Part 1) and a cohort expansion phase (Part 2). In Part 1 (Phase 1) of the study, at least 3 to 6 eligible subjects will be enrolled in sequential cohorts treated with successively higher doses of FLX475 as monotherapy or in combination with pembrolizumab (Part 1b). In Part 2 (Phase 2) of the study, expansion cohorts of both checkpoint-naïve and checkpoint-experienced patients with tumor types predicted to be enriched for Treg and/or CCR4 ligand expression (i.e. “charged tumors”) -- including both EBV+ and HPV+ tumors and NSCLC, HNSCC, and TNBC -- will be enrolled using a Simon 2-stage design. As of November 6, 2018, Cohort 1 has been completed without DLT. Clinical trial information: NCT03674567.

Download Full-text

Phase 1/2 Study of Nexi-001 Donor-Derived Multi-Antigen Specific CD8+ T Cells for the Treatment of Relapsed Acute Myeloid Leukemia (AML) after Allogeneic Hematopoietic Transplantation

Blood ◽

10.1182/blood-2021-152419 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 4819-4819

Author(s):

Monzr M. Al Malki ◽

Sumithira Vasu ◽

Dipenkumar Modi ◽

Miguel-Angel Perales ◽

Lucy Y Ghoda ◽

...

Keyword(s):

Bone Marrow ◽

T Cells ◽

T Cell ◽

Board Of Directors ◽

Cd8 T Cells ◽

Research Funding ◽

Phase 1 ◽

Clinical Activity ◽

Advisory Committees ◽

Over Time

Abstract Patients who relapse after allogeneic HCT have a poor prognosis and few effective treatment options. Responses to salvage therapy with donor lymphocyte infusions (DLI) are driven by a graft versus leukemia (GvL) effect. However, relapses and moderate to severe graft versus host disease (GVHD) are common. Therapies that increase the GvL effect without inducing GVHD are needed. The NEXI-001 study is a prospective, multicenter, open-label phase 1/2 trial designed to characterize the safety, immunogenic, and antitumor activity of the NEXI-001 antigen specific T-cell product. This product is a donor-derived non-genetically engineered therapy that consists of populations of CD8+ T cells that recognize HLA 02.01-restricted peptides from the WT1, PRAME, and Cyclin A1 antigens. These T cells consist of populations with key memory phenotypes, including stem-like memory, central memory, and effector memory cells, with a low proportion (<5%) of potentially allogeneic-reactive T-naïve cells. Patients enrolled into the first cohort of the dose escalation phase received a single infusion of 50 million (M) to 100M cells of the NEXI-001 product. Bridging anti-AML treatment was permitted during the manufacture of the cellular product with a wash-out period of at least 14 days prior to lymphodepletion (LD) chemotherapy (intravenous fludarabine 30 mg/m 2 and cyclophosphamide 300 mg/m 2) that was administered on Days -5, -4, and -3 prior to the infusion of the NEXI-001 product up to 72 hours later (Day1). Lymphocyte recovery to baseline levels occurred as early as three days after the NEXI-001 product infusion with robust CD4 and CD8 T cell reconstitution after LD chemotherapy. NEXI-001 antigen specific T cells were detectable in peripheral blood (PB) by multimer staining and were found to proliferate over time and to traffic to bone marrow. The phenotype composition of detectable antigen specific T cells at both sites was that of the infused product. T-cell receptor (TCR) sequencing assays revealed T cell clones in the NEXI-001 product that were not detected in PB of patients tested at baseline. These unique clones subsequently expanded in PB and bone marrow (BM) and persisted over time. Neutrophil recovery, decreased transfusion burden of platelets and red blood cells, and increased donor chimerism were observed. Decreases in myeloblasts and reduction in the size of an extramedullary myeloid sarcoma were suggestive of clinical activity. One patient, a 23-year- old with MRD+ disease at baseline, received two doses of 200M NEXI-001 cells separated by approximately 2 months. Following the first infusion, antigen specific CD8+ T cells increased gradually in PB to 9% of the total CD3+ T cell population just prior to the second infusion and were found to have trafficked to bone marrow. By Day 2 following the second infusion, which was not preceded by LD chemotherapy, the antigen specific CD8+ T cells again increased to 9% of the total CD3+ T cell population in PB and remained at ≥5% until the end of study visit a month later. The absolute lymphocyte count increased by 50% highlighting continued expansion of the NEXI-001 T cells. These cells also maintained significant Tscm populations. Treatment related adverse events, including infusion reactions, GVHD, CRS, and neurotoxicity (ICANS), have not developed in these patients who have received 50M to 200M T cells of the NEXI-001 product either as single or repeat infusions. In conclusion, these results show that infusion of the NEXI-001 product is safe and capable of generating a cell-mediated immune response with early signs of clinical activity. A second infusion is associated with increasing the level of antigen specific CD8+ T cells and their persistence in PB and BM. TCR sequencing and RNA Seq transcriptional profiling of the CD8+ T cells are planned, and these data will be available for presentation during the ASH conference. At least two cycles of 200M NEXI-001 cells weekly x 3 weeks of a 4-week cycle is planned for the next dose-escalation cohort. Early data suggest that the NEXI-001 product has the potential to enhance a GvL effect with minimal GVHD-associated toxicities. Disclosures Al Malki: Jazz Pharmaceuticals, Inc.: Consultancy; Neximmune: Consultancy; Hansa Biopharma: Consultancy; CareDx: Consultancy; Rigel Pharma: Consultancy. Vasu: Boehringer Ingelheim: Other: Travel support; Seattle Genetics: Other: travel support; Kiadis, Inc.: Research Funding; Omeros, Inc.: Membership on an entity's Board of Directors or advisory committees. Modi: MorphoSys: Membership on an entity's Board of Directors or advisory committees; Seagen: Membership on an entity's Board of Directors or advisory committees; Genentech: Research Funding. Perales: Sellas Life Sciences: Honoraria; Novartis: Honoraria, Other; Omeros: Honoraria; Merck: Honoraria; Takeda: Honoraria; Karyopharm: Honoraria; Incyte: Honoraria, Other; Equilium: Honoraria; MorphoSys: Honoraria; Kite/Gilead: Honoraria, Other; Bristol-Myers Squibb: Honoraria; Celgene: Honoraria; Medigene: Honoraria; NexImmune: Honoraria; Cidara: Honoraria; Nektar Therapeutics: Honoraria, Other; Servier: Honoraria; Miltenyi Biotec: Honoraria, Other. Edavana: Neximmune, Inc: Current Employment. Lu: Neximmune, Inc: Current Employment. Kim: Neximmune, Inc: Current Employment. Suarez: Neximmune, Inc: Current Employment. Oelke: Neximmune, Inc: Current Employment. Bednarik: Neximmune, Inc: Current Employment. Knight: Neximmune, Inc: Current Employment. Varela: Kite: Speakers Bureau; Nexlmmune: Current equity holder in publicly-traded company, Honoraria, Membership on an entity's Board of Directors or advisory committees.

Download Full-text

Safety and Efficacy of Venetoclax Combined with Rituximab, Ifosfamide, Carboplatin and Etoposide Chemoimmunotherapy (VICER) for Treatment of Relapsed Diffuse Large B Cell Lymphoma: Results from the Phase 1 Study

Blood ◽

10.1182/blood-2018-99-115587 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 397-397 ◽

Cited By ~ 3

Author(s):

Paolo Caimi ◽

Deepa Jagadeesh ◽

Kirsten Marie Boughan ◽

Robert M. Dean ◽

Brenda Cooper ◽

...

Keyword(s):

Board Of Directors ◽

Dose Escalation ◽

Research Funding ◽

Phase 1 ◽

B Cell Lymphoma ◽

Hematologic Toxicity ◽

Second Line ◽

Advisory Committees ◽

Line Therapy ◽

Grade 3

Abstract Introduction: Diffuse large B cell lymphoma (DLBCL) patients (pts) with relapsed or refractory (r/r) disease after front line chemoimmunotherapy have poor survival. Standard second line therapy for r/r DLBCL consists of platinum-based chemotherapy followed by autologous stem cell transplant (ASCT). Approximately 50% of pts do not respond to second line therapy, highlighting the need for increased efficacy of these regimens. The antiapoptotic protein Bcl-2 is overexpressed in approximately 30% of DLBCL cases. Preclinical and early clinical data suggest that addition of venetoclax (VEN), a potent selective Bcl-2 inhibitor, to chemoimmunotherapy augments response rates and durability in lymphoma. We conducted a phase 1 dose escalation and dose expansion study to evaluate the safety and efficacy of VEN in combination with R-ICE (rituximab, ifosfamide, carboplatin and etoposide) (VICER) r/r DLBCL pts. Here we present the results after completion of VEN dose escalation. Methods: Patients (≥18 years of age) with r/r DLBCL who failed one or two lines of therapy were enrolled. The primary objective was to determine the recommended phase 2 dose (RP2D) of VEN when combined with R-ICE. VEN was given orally on days 1 - 10 of each 21 - day cycle x 3 cycles. Dose escalation was conducted according to a 3+3 design, with 3 dose levels (400, 600 and 800mg). R-ICE was given at standard dose and schedule on days 1 - 3 of each cycle for 3 cycles. No intra-patient dose escalation was allowed. Tumor lysis syndrome (TLS) mitigation included inpatient administration, hydration, allopurinol and frequent laboratory evaluation during cycle 1. All patients received pegfilgrastim; use of prophylactic antibiotics during neutropenia was left at the discretion of the treating physician. Results: As of July 20, 2018, 18 pts with DLBCL (14 male, 4 female) were enrolled (VEN 400mg, n = 3; 600 mg, n = 3; 800 mg, n = 12). Median age of pts was 55.5 years [range 27-78]. All pts received rituximab and anthracycline containing first - line therapy, 4 patients had failed a second line of therapy. One patient experienced dose limiting toxicity (DLT) at 800 mg VEN, with acute renal failure, febrile neutropenia, sepsis and rapid tumor progression and died after cycle 1. No other DLTs were observed. Hematologic toxicity was common, with grade ≥3 anemia in 6 (33%) pts; grade ≥3 neutropenia in 14 (78%) pts and grade ≥3 thrombocytopenia in 10 (55%) pts. Five (28%) pts experienced febrile neutropenia. The most common non-hematologic all-grade treatment emergent adverse events (TEAEs) were fatigue (7 [38%] pts), nausea (6 [33%] pts); diarrhea (6 [33%] pts), anorexia (5 [27%] pts], infection (5 [27%] pts) and sensory neuropathy (5 [27%] pts). Grade ≥3 TEAEs included infection (4 [22%] pts), cholecystitis (2 [11%]) and one case each (5.5%) of peripheral edema, acute renal failure, acute coronary syndrome, atrial fibrillation, hyponatremia and hypokalemia. One case of laboratory TLS occurred, but no clinical TLS was observed. At data cutoff, the intent-to-treat (ITT) population included 13 patients that had at least one cycle of therapy and end of treatment response or had discontinued prior to response assessment; 3 pts did not complete all planned cycles of VICER: one patient died after DLT, one patient proceeded to ASCT in complete remission (CR) after 2 cycles and another withdrew after cycle 1, achieving partial remission (PR) with additional 2 cycles of R-ICE. Nine pts (69%) achieved CR and 2 (15%) achieved PR (overall response rate (ORR): 11/13 [84.6%]) (Tables 2 and 3). Figure 1 depicts tumor response data. Among 11 responding pts, 7 have undergone stem cell collection, with a median CD34 cell count of 3.73x106 cells/kg. Seven pts have completed their ASCT, with hematopoietic engraftment in all cases. Median follow up of patients in CR/PR is 6 months (range 1 - 12), none has experienced progression. Conclusions: In this Phase 1 study, VICER shows encouraging antilymphoma activity in r/r DLBCL, including double hit/double expressor lymphomas, with high rates of complete metabolic response (69% CR by PET), which is higher than historical levels reported with R-ICE alone (CR typically <45%). The RP2D of VEN is 800 mg. Hematologic toxicity - particularly neutropenia - is common, and G-CSF support as well as antibiotic prophylaxis are necessary to prevent infectious complications. Updated safety, progression-free survival and response data will be presented at the meeting. Disclosures Caimi: Kite Pharma: Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Research Funding; Celgene: Speakers Bureau. Hill:Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: 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; Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: 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; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Download Full-text

Trial in Progress: Phase I Dose-Escalation and Dose-Expansion Trial of a Novel Glutaminase Inhibitor (CB-839 HCl) in Combination with Carfilzomib and Dexamethasone in Relapsed and/or Refractory Multiple Myeloma

Blood ◽

10.1182/blood-2019-123399 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3160-3160

Author(s):

Wilson I Gonsalves ◽

Srinivas Devarakonda ◽

Rachid Baz ◽

Natalia Neparidze ◽

Alex A Adjei ◽

...

Keyword(s):

Multiple Myeloma ◽

Board Of Directors ◽

Dose Escalation ◽

Mitochondrial Respiration ◽

Research Funding ◽

Phase 1 ◽

Tca Cycle ◽

Glutamine Metabolism ◽

Cellular Respiration ◽

Advisory Committees

Background: c-MYC activation is an early event of myeloma pathogenesis. It upregulates the expression of the glutaminase 1 (GLS1) enzyme which converts glutamine to glutamate in the mitochondria. Glutamate is required for the biosynthesis of various molecules in the tricarboxylic acid (TCA) cycle (i.e., glutamine anaplerosis). CB-839 HCl is a first-in-class, orally available, selective, noncompetitive inhibitor of GLS1. This inactivation of GLS1 results in an increase of glutamine and a decrease of glutamate and several TCA cycle intermediates within cancer cells, leading to a decrease in their proliferation and/or an increase in cell death. In the phase 1 study, CX-839-002, the safety and tolerability of CB-839 HCl was evaluated in patients with hematological tumors (multiple myeloma (MM) and non-Hodgkin's lymphoma), either as monotherapy or in combination with pomalidomide and dexamethasone or with dexamethasone alone. It was determined to be well tolerated and the maximal tolerated dose (MTD) was not reached. Proteasome inhibitors (PI) are the cornerstone agents in the treatment of myeloma. They disrupt normal protein homeostasis causing an induction of cellular proteotoxic stress, thus, making it an effective strategy against myeloma plasma cells, which naturally mass-produce large quantities of immunoglobulin proteins. PI-resistant MM cells are associated with changes in cellular bioenergetics that favor the increased use of mitochondrial respiration for energy production. Given the increased reliance of PI-resistant MM cells on mitochondrial respiration, and the critical role of glutamine for cellular respiration, inhibition of glutamine metabolism is a rational molecular strategy for the treatment of PI-resistant MM. Furthermore, pre-clinical studies demonstrate the in vitro and ex vivo synergism of CB-839 HCl with carfilzomib (CFZ) in terms of its cytotoxicity and anti-proliferation capacity in various primary human myeloma cell lines and primary patient myeloma cells respectively. As a result, this novel combination of glutaminase inhibition with proteasome inhibition appears promising as a therapeutic combination in MM and warrants further clinical investigation. Methods: This study is a phase 1, multicenter clinical trial of CB-839 HCl in combination with carfilzomib and dexamethasone for patients with relapsed and/or refractory myeloma. Part A of this trial is a 3+3 dose escalation design and Part B is a dose expansion cohort at the RP2D determined in Part A. Up to a maximum of 42 patients will be enrolled at participating ETCTN sites. CFZ will be administered in its usual weekly dosing schedule of days 1, 8 and 15 of a 28 day schedule along with dexamethasone on days 1, 8, 15 and 22. CB-839 will be started at a dose level of 400 mg twice daily and will be investigated to a maximum dose of 800 mg twice daily. Prior to day 1 of Cycle 1, we will administer a 7 day lead in of CB-839 monotherapy before combining it with CFZ. Key inclusion criteria are having relapsed/refractory myeloma with at least 2 prior lines of therapy and prior exposure to PIs, immunomodulators and Anti-CD38 monoclonal antibodies, having measurable disease, adequate hematologic reserve, kidney function and liver function. Key exclusion criteria are being refractory or intolerant to CFZ, adverse cardiac history, central nervous system disease and AL amyloidosis. The primary objective of this trial is to determine the MTD or recommended phase II dosing (RP2D) of CB-839 HCl in combination with carfilzomib and dexamethasone. The secondary objective is to evaluate the safety and tolerability as well as the overall response rate (ORR) associated of CB-839 HCl in combination with carfilzomib and dexamethasone. Correlative objectives will evaluate plasma pharmacokinetic profiles of CB-839 HCl and carfilzomib when used in combination. They will also evaluate potential predictive and prognostic biomarkers as well as resistance mechanisms using genomic DNA, RNA, flow cytometry, immunohistochemistry and metabolomics-based assessment platforms. Recruitment is ongoing and this trial is registered on clinicaltrials.gov: NCT03798678. Disclosures Baz: Bristol-Myers Squibb: Research Funding; Sanofi: Research Funding; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Research Funding; Merck: Research Funding. Neparidze:Janssen Scientific Affairs, LLC: Research Funding; Eidos Therapeutics: Other: Member of Independent Diagnostic Committee; MMRF/Synteract: Membership on an entity's Board of Directors or advisory committees. Kumar:Janssen: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Takeda: Research Funding.

Download Full-text

Nivolumab for Relapsed or Residual Haematological Malignancies after Allogeneic Haematopoietic Stem Cell Transplantation (NIVALLO)

Blood ◽

10.1182/blood-2018-99-112310 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 4633-4633 ◽

Cited By ~ 4

Author(s):

Eric Wong ◽

Emily Dawson ◽

Joanne Davis ◽

Rachel Koldej ◽

Mandy Ludford-Menting ◽

...

Keyword(s):

Clinical Trial ◽

T Cells ◽

Stem Cell ◽

T Cell ◽

Board Of Directors ◽

Cd8 T Cells ◽

Acute Gvhd ◽

Haematological Malignancies ◽

Advisory Committees ◽

Safety And Efficacy

Abstract Aim: To evaluate the safety and efficacy of nivolumab for the treatment of relapsed or residual haematological malignancies after allogeneic stem cell transplantation (alloSCT). Background: Relapse of haematological malignancies following alloSCT is a major cause of post-transplant mortality. Interaction between programmed cell death protein-1 (PD-1) and its ligand (PD-L1) inhibits T-cell alloreactivity and contributes to immune escape. Nivolumab inhibits PD-1 signalling and augments T-cell cytotoxicity. The safety and efficacy of nivolumab post-alloSCT has not been evaluated in a clinical trial. Method: In this investigator-initiated phase IIa clinical trial, patients with relapsed or persistent haematological malignancies following alloSCT receive nivolumab 3mg/kg for up to 48 weeks. Patients with current graft-versus-host disease (GVHD) or prior grade ≥2 acute GVHD or chronic GVHD are excluded. Results: Six participants have received at least one dose of nivolumab at this interim assessment. Primary haematological malignancies relapsing post-alloSCT included Hodgkin lymphoma (HL, 2 patients), acute myeloid leukaemia (AML, 2), transformed chronic lymphocytic leukaemia (tCLL, 1) and mantle cell lymphoma (MCL, 1). The median time from alloSCT to first dose of nivolumab was 25.5 months. Two participants developed grade 3 acute GVHD at 6 days and 13 days following the first dose of nivolumab. Complete or partial responses were observed in 3 participants (50%). Two participants with HL achieved complete responses. One participant with MCL had a complete nodal response with small volume persistent bone marrow disease. One participant with monosomal karyotype AML achieved initial blast reduction (23% to 13%) however subsequently developed progressive AML. T-cell phenotyping at first AML relapse (prior to nivolumab) demonstrated a high proportion of CD8+ T cells that expressed PD-1 and T-cell immunoglobulin and mucin domain 3 (TIM-3) consistent with T-cell exhaustion. Following treatment with nivolumab there was an increase in TNFα production by CD8+ T-cells at day 7 post nivolumab, demonstrating augmentation of T-cell activity. Despite continued nivolumab treatment TNFα production subsequently declined and correlated with loss of clinical response. TIM-3 expression was further upregulated at post-nivolumab progression suggesting this inhibitory checkpoint receptor may have contributed to nivolumab resistance. Conclusion: Nivolumab treatment after alloSCT results in potent immune stimulation with a high rate of clinical responses, albeit with a risk of GVHD. Acquired resistance to nivolumab may develop via upregulation of alternative inhibitory checkpoints. Disclosures Szer: Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria, Other: Travel Support , Research Funding. Grigg:BMS: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees.

Download Full-text