scholarly journals Phase 1 Results of Anti-PD-Ligand 1 (Durvalumab) & Lenalidomide in Patients with Cutaneous T Cell Lymphoma and Correlation with Programmed Death Ligand 1 Expression and Gene Expression Profile

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 20-20
Author(s):  
Christiane Querfeld ◽  
Ni-Chun Tsai ◽  
Joycelynne Palmer ◽  
Xochiquetzal U. Martinez ◽  
Farah Abdulla ◽  
...  
Keyword(s):  
Gene Expression ◽  
Antitumor Activity ◽  
Gene Expression Profile ◽  
Dose Level ◽  
Expression Profile ◽  
Phase 1 ◽  
Phase 2 ◽  
Level 3 ◽  
Level 1 ◽  
Level 2

Background:T cells in CTCL 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. We initiated a phase 1/2 clinical trial of lenalidomide and durvalumab (NCT03011814) to determine the safety and efficacy of this regimen. Durvalumab is a human monoclonal antibody with high affinity and selectivity for PD-L1, targeting exhausted T cells and distinct cells within their environment. Lenalidomide, an oral immunomodulatory drug (IMiD) 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. Associations between immune checkpoints, gene expression profile and the clinical efficacy of durvalumab/ lenalidomide combination were evaluated. The primary objectives were to determine the recommended phase 2 dose of lenalidomide in combination with durvalumab and safety with primary endpoint of toxicity (using CTCAE 4.03). Secondary end points included objective response rate (ORR) and median duration. Relationships between gene expression profile (GEP), PD-L1 expression, and antitumor activity were exploratory end points. Methods:Phase 1 portion to evaluate the safety and tolerability of the durvalumab and lenalidomide combination has completed enrollment. Pts were enrolled in sequential cohorts to receive durvalumab (fixed dose at 1500 mg) and dose escalation of lenalidomide (dose level 1 = 10 mg for all cycles; dose level 2 = 10 mg for cycle 1, 15 mg for all subsequent cycles; dose level 3 =10 mg for cycle 1, 15 mg for cycle 2, and 20 mg for all subsequent cycles) to characterize safety, efficacy and antitumor activity. Serial skin samples were collected to assess the impact on the tumor microenvironment and anti-tumor activity. Results:Thirteen pts. were evaluable for toxicities and 12 patients evaluable for response. 10 males/3 females, median age 36 (29-72 y), with aggressive or refractory/advanced CTCL, clinical stages IB (2), IIA (3), IIB (6), IIIA (1), and aggressive epidermotropic CD8+ CTCL (1) and a median of prior systemic treatments of 3 (range, 2-8) have been enrolled. Dose level 1 (n=3), dose level 2 (n= 3), dose level 3 (n=4). Median follow up time was 16.1 months (range, 3.7-36.1) months. No serious AEs or DLTs were observed during the DLT evaluation period (cycles 1-3). The most frequently reported AEs were fatigue (n=8), skin pain (n=4), chills (n=3), anemia (n=3), and leukopenia (4). One grade 3 maculopapular rash (possibly due to lenalidomide) was observed, all other treatment-related AEs were grade 1/2 in severity. One patient discontinued treatment due to fatigue. Three patients developed grade 1/2 autoimmune thyroiditis that resolved with treatment. Median cycles of treatment were 7 (range, 1-28). Median duration of response was 6 (range, 1- 28+) months. Nine pts achieved PR, 2 pts maintained stable disease and 2 pts developed PD. Five pts remain on treatment. Gene expression levels for several checkpoints (PD1, PD-L1 & ICOS) (Cycle1 Day1 vs Cycle 2 Day15) were analyzed. Gene expression profile highlights downregulation of TNF-alpha signaling via NFkB, IFN-gamma, and PI3-AKT-mTOR signaling pathways in responders; up-regulation of MYC targets, IL2-, JAK-STAT and pro-inflammatory pathways were seen in PD compared to responders. Conclusions:Anti-PD-L1/lenalidomide has significant clinical activity in refractory/advanced CTCL, which will be formally evaluated in the Phase 2 portion. Responses were durable and ongoing, and treatment was well tolerated. Dose escalation is up to maximum dose of 20 mg lenalidomide daily. Our preliminary results reveal adaptive and innate immune signatures that may be predictive of response to checkpoint blockade and yield insights into mechanisms of therapeutic resistance. Disclosures Querfeld: MiRagen:Consultancy;Stemline:Consultancy;Trillium:Consultancy;Celgene:Research Funding;Kyowa Kirin:Consultancy;Helsinn:Consultancy;Bioniz:Consultancy.Abdulla:Johnson Johnson:Research Funding;Mallinckrodt:Consultancy, Speakers Bureau.Rosen:Seattle Genetics:Consultancy;NeoGenomics:Consultancy;Aileron Therapeutics:Consultancy;Novartis:Consultancy;Pebromene:Consultancy;Celgene:Speakers Bureau;paradigm Medical Communications:Speakers Bureau;Abbvie:Speakers Bureau.Zain:Mundi Pharma:Research Funding;Seattle Genetics:Research Funding;Kyowa Kirin:Research Funding.

scholarly journals Phase 1 Results of Anti-PD-Ligand 1 (Durvalumab) & Lenalidomide in Patients with Cutaneous T Cell Lymphoma and Correlation with Programmed Death Ligand 1 Expression and Gene Expression Profile

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4024-4024
Author(s):  
Christiane Querfeld ◽  
Xiwei Wu ◽  
Tracy Stiller ◽  
Joycelynne Palmer ◽  
James F Sanchez ◽  
...  
Keyword(s):  
Gene Expression ◽  
T Cells ◽  
Board Of Directors ◽  
Gene Expression Profile ◽  
Dose Level ◽  
Expression Profile ◽  
Research Funding ◽  
Phase 1 ◽  
Phase 2 ◽  
Advisory Committees

Background: T cells in CTCL 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. 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, targeting exhausted T cells and distinct cells within their environment. Lenalidomide, an oral immunomodulatory drug (IMiD) 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. Associations between immune checkpoints, gene expression profile and the clinical efficacy of durvalumab/lenalidomide combination were evaluated. The primary objectives were to determine the recommended phase 2 dose of lenalidomide in combination with durvalumab and safety with primary endpoint of toxicity (using CTCAE 4.03). Secondary end points included objective response rate (ORR) and median duration. Relationships between gene expression profile (GEP), PD-L1 expression, and antitumor activity were exploratory end points. Methods: A Phase 1 portion (NCT03011814) is ongoing to evaluate the safety and tolerability of the durvalumab and lenalidomide combination. Pts are enrolled in sequential cohorts to receive durvalumab (fixed dose at 1500 mg) and dose escalation of lenalidomide (dose level 1 = 10 mg for all cycles; dose level 2 = 10 mg for cycle 1, 15 mg for all subsequent cycles; dose level 3 =10 mg for cycle 1, 15 mg for cycle 2, and 20 mg for all subsequent cycles) to characterize safety, efficacy and antitumor activity. Serial skin samples were collected to assess the impact on the tumor microenvironment and anti-tumor activity. Results: Ten pts. were evaluable for toxicities. Nine patients were evaluable for response with three patients at each dose level. 8 males/2 females, age 29-59 y, with refractory/advanced CTCL, clinical stages IB (1), IIA (3), IIB (4), IIIA (1), and aggressive epidermotropic CD8+ CTCL (1) and a median of prior systemic treatments of 3 (range, 2-4) have been enrolled. Median follow up time was 12 (range, 3-24+) months. No serious AEs or DLTs were observed during the DLT evaluation period (cycles 1-3). The most frequently reported AEs were fatigue (n=7), skin pain (n=4), chills (n=3), anemia (n=3), and leukopenia (4). One grade 3 maculopapular rash (possibly due to lenalidomide) was observed, all other treatment-related AEs were grade 1/2 in severity. Median cycles of treatment were 7 (range, 3-20+) months. Median duration of response was 4 (range, 1- 21+) months. Six pts achieved PR, while 3 pts maintained stable disease. Three pts remain on treatment. Expression panels of several checkpoints (PD1, PD-L1 & ICOS) (Cycle1 Day1 vs Cycle 2 Day15) were analyzed. Detectable levels of PD-L1 but low levels of ICOS are observed in responding pts vs. high PD-L1 and ICOS levels in non-responders. GEP highlights downregulation of TNF-alpha signaling via NFkB, IFN-gamma, and PI3-AKT-mTOR signaling pathways among other pathways. Conclusions: Durvalumab/lenalidomide has significant clinical activity in refractory/advanced CTCL, which will be formally evaluated in the Phase 2 portion. Responses were durable and ongoing, and treatment was well tolerated. Dose escalation is up to lenalidomide 20 mg daily. Our preliminary results from pts 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: Bioniz: Membership on an entity's Board of Directors or advisory committees, Other: Investigator; Soligenix: Other: Investigator; Celgene: Other: Investigator, Research Funding; City of Hope Cancer Center and Beckman Research Institute: Employment; Medivir: Consultancy; Trillium: Consultancy, Other: Investigator, Research Funding; miRagen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Investigator; Kyowa: Membership on an entity's Board of Directors or advisory committees, Other: Investigator; Eisai: Other: Investigator; Elorac: Other: Investigator, Research Funding; Helsinn: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Investigator. Palmer:Gilead Sciences: Consultancy. Zain:Spectrum: Consultancy; Seattle Genetics: Consultancy.

Phase 1 Trial of Sorafenib and Everolimus In Patients with Lymphoma or Multiple Myeloma.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2802-2802 ◽  
Author(s):  
Shaji Kumar ◽  
Luis F Porrata ◽  
Stephen M. Ansell ◽  
Joseph P Colgan ◽  
Betsy LaPlant ◽  
...  
Keyword(s):  
Disease Progression ◽  
Dose Level ◽  
Research Funding ◽  
Phase 1 ◽  
Hematologic Toxicity ◽  
Phase 2 ◽  
Level 3 ◽  
Level 1 ◽  
Grade 3 ◽  
Level 2

Abstract Abstract 2802 Background: Redundancy of pro-survival signaling pathways promotes survival and drug resistance in lymphoid and plasma cell malignancies. In particular, the PI3K-Akt and the MEK-ERK pathways have been shown to play an important role in the proliferation and survival of these malignant cells induced by various cytokines in the tumor microenvironment. Sorafenib, a Raf kinase and VEGF receptor inhibitor, and everolimus, an mTOR inhibitor, have synergistic cytotoxicity in myeloma and lymphoma cells due to inhibition of multiple signaling pathways. Methods: We designed a Phase 1/2 clinical trial to identify the maximum tolerated doses of the two drugs used in combination and the efficacy of the combination. Patients (Pts) with relapsed myeloma or lymphoma were eligible for enrollment. Pts were required to have an absolute neutrophil count ≥1500 × 10(6)/L, a platelet count ≥75,000, and a serum creatinine 21.5 mg/dL. The study utilized the classic 3+3 design. Extensive pharmacokinetic studies were performed to better delineate potential drug interactions. Results: Twenty-six pts were accrued from August 2007 to February 2009. Four pts discontinued sorafenib during cycle 1 for various reasons (2 patient refusal, 1 unrelated medical condition and 1 physician discretion) and were excluded from MTD determination. An additional pt did not have measurable disease and was ineligible, leaving 19 pts with lymphoma (including 6 with Hodgkin lymphoma) and 2 with myeloma for phase I analysis. The pts had a median age of 56 years (range, 22, 69) and were heavily pretreated with a median of 4 prior therapies (range, 1–10). Eighteen (86%) had received a prior stem cell transplant. Four dose limiting toxicities were seen across all dose levels (Table). These included grade 3 vomiting (level 1), grade 4 thrombocytopenia (level 2 and 3, one each) and grade 2 hand and foot rash leading to treatment delay (level 3). Overall, 13 pts experienced a grade 3 or 4 hematologic toxicity. Grade 3 or 4 anemia, neutropenia, and thrombocytopenia occurred in 19%, 43%, and 38% of pts, respectively. Four pts have experienced a grade 3 non-hematologic toxicity; no grade 4 non-hematologic toxicities were seen. Grade 3 non-hematologic toxicities included hypokalemia, weight loss, vomiting, hand-foot skin reaction, fatigue, and elevated alkaline phosphatase. Dose level 1 (sorafenib 200 mg and everolimus 5 mg daily) was best tolerated and was selected for phase 2 evaluation. The ORR was 33% (7/21;95% CI: 15–57%, Table) with 3 pts at dose level 0 (2 PR, 1 CR), one at level 2 (1 PR) and three at level 3 (2 PR, 1 CR) responding. The responders included 5 pts with Hodgkin's disease and one each with an NK cell and T-cell lymphoma. Pts have received a median of 6 cycles (range: 1–19) of treatment. 16 pts have discontinued treatment due to disease progression (13 pts), non-resolution of cytopenias (1 pt), physician discretion (1 pt), and death on study due to lymphoma (1 pt). Disease progression has been seen in 16 pts; 9 pts have died. Median follow-up for pts still alive is 18.7 months (range: 11.5–29.4). 6 pts died from disease progression, one each due to sepsis unlikely related to treatment, cholecystitis, and unknown causes. Sorafenib is metabolized by the cytochrome P450 CYP3A enzyme and RAD-001 mainly by the CYP3A4 system in the liver, hence there is a potential for interactions. The detailed PK analyses performed as part of this trial showed a decrease in the RAD001 levels following initiation of sorafenib on day 8 of cycle 1 (Figure). Conclusion: The combination of sorafenib and everolimus is safe at a recommended phase 2 dose of sorafenib 200 mg and everolimus 5 mg daily. There is no significant drug interaction seen. Activity has been observed, especially in the setting of Hodgkins Disease. Disclosures: Kumar: Celgene: Consultancy, Research Funding; Millennium: Research Funding; Merck: Consultancy, Research Funding; Novartis: Research Funding; Genzyme: Consultancy, Research Funding; Cephalon: Research Funding. Off Label Use: Lenalidomide for treatment of newly diagnosed myeloma. Witzig:Novartis and Celgene: Patents & Royalties, Research Funding, Served on advisory boards with Novartis and Celgene – both uncompensated with compensation to Mayo Clinic.

A phase IB trial of 5-azacitidine (5AC) and suberoylanilide hydroxamic acid (SAHA) in patients with metastatic or locally recurrent nasopharyngeal carcinoma (NPC) and NK-T cell lymphoma.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e17017-e17017
Author(s):  
Wen Son Hsieh ◽  
Eng Huat Tan ◽  
Wan-Teck Lim ◽  
Ross A. Soo ◽  
Anthony T. C. Chan ◽  
...  
Keyword(s):  
Gene Expression ◽  
Viral Load ◽  
Dose Level ◽  
Clinical Benefit ◽  
Tumor Tissue ◽  
Level 3 ◽  
Level 1 ◽  
Grade 3 ◽  
Level 2

e17017 Background: Epigenetic up-regulation of EBV and cellular genes via demethylation and histone deacetylase inhibition can induce EBV lytic replication enhancing immune mediated tumor killing and up-regulation of tumor suppressor genes resulting in tumor apoptosis. Methods: Patients (Pt) with relapsed or refractory NPC and NK-T cell lymphomas were enrolled to determine safety, tolerability, pharmacokinetics (PK), pharmacodynamics and preliminary anti-tumor activity using a dose escalation design. 5AC was administered on days 1 to 10 sub-cutaneously while SAHA was administered on days 1 to 14 orally. PK for SAHA, EBV viral load, characterization of circulating EBV, Immunohistochemistry (IHC) and EBV promoter methylation analysis in tumor tissue were performed. Results: 11 pt have been treated (M:F 8:3, median age 48, R: 35-71) at 3 dose levels – 5AC 50 mg/m2 and SAHA 200 mg b.i.d. (dose level 1), 5AC 37.5 mg/m2 and SAHA 200 mg q. am and 100 mg q. pm (dose level 2), and 5AC 25 mg/m2 and SAHA 100 mg b.i.d (dose level 3). Median number of previous treatment regimens was 3 (R:1-6). Dose limiting toxicities (DLT) were seen in 2/2 pts at dose level 1: grade 4 thrombocytopenia (1 pt), grade 3 nausea, vomiting and fatigue (2 pts), and grade 5 hepatic failure (1 pt). Two of six patients at dose level 2 experienced DLT: grade 3 fatigue (1 pt) and worsening of pre-existing Sweet’s Syndrome (1 pt). Common AEs (G1/2) included fatigue (73%), cough (64%), anorexia (55%), and injection site reaction (45%). One minor response was seen and 5 pt had prolonged stable disease (>16 weeks), including one patient for 88 weeks. Analysis of post-treatment tumor biopsies showed demethylation of EBV lytic cycle gene promoters after treatment. SAHA PK, IHC results for EBV gene expression in tumor tissue, EBV viral load and characterization of circulating EBV will be presented. Conclusions: 5AC/SAHA appears to be tolerable at dose level 3 with suggestion of clinical benefit. Analysis of post-treatment tumor and blood samples suggests that modulation of EBV gene expression may play a role in the mechanism underlying clinical benefit. Continued accrual at dose level 3 is ongoing. Clinical trial information: NCT00336063.

A Phase 1 Trial of Vorinostat and Pegylated Liposomal Doxorubicin In Relapsed or Refractory Lymphoma.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2816-2816
Author(s):  
Frederick Lansigan ◽  
Stuart Seropian ◽  
Dennis L. Cooper ◽  
Von Potter ◽  
Noelle Sowers ◽  
...  
Keyword(s):  
Dose Level ◽  
Phase 1 ◽  
Pegylated Liposomal Doxorubicin ◽  
Cell Transplant ◽  
Heavily Pretreated ◽  
Level 3 ◽  
Refractory Lymphoma ◽  
Level 1 ◽  
Grade 3 ◽  
Level 2

Abstract Abstract 2816 Background: Vorinostat is a histone deacetylase inhibitor with activity in lymphoma and leukemia. Vorinostat has been reported to act synergistically with topoisomeraseII inhibitors such as anthracyclines (Ac) by facilitating an open chromatin configuration thus enhancing double-strand DNA breaks and apoptosis. We conducted a phase 1 study of escalating doses of vorinostat with pegylated liposomal doxorubicin (V+PLD) in patients with relapsed or refractory lymphoma. The primary objective was to determine the maximum tolerated dose (MTD). Other endpoints included safety, tolerability, and activity of V+PLD. Methods: Patients age ≥18 years with relapsed or refractory lymphoma were enrolled sequentially into 1 of 3 dosing levels using a standard 3+3 design for up to 8 cycles. The study was conducted in accordance with the Declaration of Helsinki, good clinical practice and regulatory guidelines. Vorinostat 200 (dose level 1), 300 (dose level 2), or 400mg (dose level 3) twice daily on days 1–7 and PLD 30mg/m2 on day 3 of a 21-day cycle were administered to eligible and consenting patients. CTCAE v.3.0 was used to determine toxicities, and the revised criteria for malignant lymphoma were used to determine response. Results: 14 patients have been enrolled; 2 men and 12 women; median age 69 years [range 27–88]; median prior therapies (4) [1-11]; prior Ac (13); median prior Ac dose (300mg/m2) [108-440mg/m2]; prior HDACi (1); Dose level 1 (7); Dose level 2 (4); Dose level 3 (3). Lymphoma subtypes included: Hodgkin's lymphoma (HL)(4), peripheral T-cell lymphoma (3), diffuse large B-cell lymphoma (DLBCL)(5), grey zone lymphoma (1), lymphoplasmacytic lymphoma (1). Median number of study cycles was two [1-8](2). Grade 3–4 hematologic toxicities included: neutropenia (3) and thrombocytopenia (1). Grade 3–4 non-hematologic toxicities included: fatigue (2), nausea (1), anorexia (1), dehydration (1), AST/ALT elevation (1), amylase/lipase elevation (1). No cardiac toxicities were observed. There was one death attributed to disease progression. Partial responses (PR) were documented in two HL patients, stable disease (SD) in one HL and one DLBCL patient. Three patients continued therapy beyond 2 cycles. One HL patient with a PR tolerated 8 cycles despite a prior anthracycline dose of 350mg/m2 and 9 prior systemic treatments including ABVD, ICE, GND, DICEP, BEAM and autologous stem cell transplant, Gem and C-MOPP. Another HL patient with a PR after 2 cycles is currently on cycle 3 at dose level 3 and had 5 prior treatments including autologous transplant. One other HL patient with SD discontinued therapy after 2 cycles to proceed with alternative chemotherapy including allogeneic stem cell transplant. One patient with cutaneous DLBCL obtained a skin response but had overall stable disease and completed 6 cycles before disease progression; prior treatment included R-CHOP, R-ICE, CEPP, and GemOx. In addition, one patient with lymphoplasmacytic lymphoma had a clinical response after 1 cycle but therapy was discontinued because of neutropenia and her disease progressed. Conclusions: The combination of V+PLD is well tolerated even among older and heavily pretreated patients. There were no cardiac toxicities even in patients heavily pretreated with anthracyclines. The MTD has not been reached and enrollment to dose level 3 is ongoing. Disease control was achieved in 4 of 14 patients (2 PR and 2 SD). Of interest, 3 of 4 patients with HL achieved disease control (2 PR and one SD), and treatment with vorinostat in combination with anthracycline-based therapy warrants further investigation in HL. Disclosures: Lansigan: Merck: Speakers Bureau. Off Label Use: Vorinostat in combination with pegylated doxorubicin is considered experimental in lymphoma. Foss:Merck: Speakers Bureau.

scholarly journals ACTR-63. PHASE I DOSE ESCALATION STUDY OF PROCASPASE ACTIVATING COMPOUND-1 (PAC-1) IN COMBINATION WITH TEMOZOLOMIDE IN PATIENTS WITH RECURRENT ANAPLASTIC ASTROCYTOMA OR GLIOBLASTOMA

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi28-vi28
Author(s):  
Matthias Holdhoff ◽  
Martin Nicholas ◽  
Richard Peterson ◽  
Oana Danciu ◽  
Stefania Maraka ◽  
...  
Keyword(s):  
Dose Level ◽  
Dose Escalation ◽  
Anaplastic Astrocytoma ◽  
Caspase 3 ◽  
Phase 1 ◽  
Maximum Tolerated Dose ◽  
Pharmacokinetic Data ◽  
Dose Escalation Study ◽  
Level 1 ◽  
Level 2

Abstract BACKGROUND Procaspase activating compound -1 (PAC-1) is a small molecule that catalyzes conversion of procaspase-3 to caspase-3 which induces apoptosis in cancer cells. Glioblastoma (GBM) is among the tumors with high concentrations of procaspase-3 and low levels of caspase-3. PAC-1 crosses the blood brain barrier and has been shown to synergize with temozolomide (TMZ) in canine malignant glioma and meningioma that arise spontaneously. METHODS This is a multicenter phase 1 dose-escalation study to assess the maximum tolerated dose (MTD) of PAC-1 administered days 1–21 in combination with TMZ days 8–12 at a dose of 150 mg/m2 of each 28 day cycle in subjects with recurrent anaplastic astrocytoma (AA) or GBM. A modified Fibonacci 3 + 3 design is used with up to 4 dose levels of PAC-1 (375, 500, 625 and 750 mg/day). Neurologic toxicity, including cognitive function, is closely monitored throughout the trial. INTERIM DATA: A total of 14 subjects have been enrolled to-date. Of these, 7 at dose level 1, PAC-1 375 mg/day (6 GBM, 1 AA; median age 58y, range 25–75) and 7 at dose level 2, PAC-1 500 mg/day (5 GBM, 2 AA; median age 51y, range 35–60). Best responses to-date were 2 subjects with a partial response and 2 with stable disease. Grade 3 (hepatotoxicity) and 4 (cerebral edema) was reported as possibly related to PAC-1 in 1 patient at dose level 1. The median number of cycles received was 4 (range, 1–12+) at dose level 1 and 2 (range, 1–3) at dose level 2. Enrollment to dose level 2 has been completed and data analysis is ongoing. Updated response and toxicity as well as pharmacokinetic data will be presented.

Oxaliplatin, Fludarabine, Cytarabine, and Rituximab Combination Therapy Induces High Response Rates in Agressive Chronic Lymphocytic Leukemia (CLL) and Richter's Syndrome (RS).

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3443-3443 ◽  
Author(s):  
Apostolia-Maria Tsimberidou ◽  
William Wierda ◽  
William Plunkett ◽  
Susan O'Brien ◽  
Thomas J. Kipps ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Level ◽  
Phase Ii ◽  
Research Funding ◽  
Response Rates ◽  
Off Label ◽  
Level 3 ◽  
Level 1 ◽  
Grade 3 ◽  
Level 2

Abstract Abstract 3443 Poster Board III-331 Introduction The first Phase I-II clinical trial of oxaliplatin, fluradabine, cytarabine (Ara-C), and rituximab (OFAR1) demonstrated significant activity in refractory CLL and RS (Tsimberidou et al, J Clin Oncol, 2008;26:196). To enhance the response rate and decrease myelosuppression, the dose of oxaliplatin was increased to 30mg daily, the dose of Ara-C was decreased to 0.5g/m2 daily and the optimal number of days of fluradabine and Ara-C administration was explored (OFAR2). Methods In a Phase I-II study of OFAR2, patients were treated with oxaliplatin 30mg/m2, D1-4; fludarabine 30mg/m2, Ara-C 0.5g/m2; rituximab 375mg/m2, D3; and pelfigrastim 6mg, D6. Fludarabine and Ara-C were given on D2-3 (dose level 1) D2-4 (dose level 2) or D2-5 (dose level 3); courses were repeated every 4 weeks. Patients received prophylaxis for tumor lysis, DNA viruses, and PCP. A “3+3” design was used and the planned number of patients in the Phase II was 90 (CLL, 60; RS, 30). Results Ninety-one patients (CLL, 67; RS, 24) have been treated to date: Phase I, 12 patients (by dose level: 1, n=3; 2, n=6; and 3, n=3). DLTs were noted in 2 of 3 patients on dose level 3 (G4 diarrhea, 1; G4 neutropenic sepsis, 1); thus, dose level 2 was the MTD. Seventy-nine patients (relapsed CLL, 58; RS, 19) have been treated in the Phase II portion of the study. Patient characteristics were as follows: age > 60 years, 65%; 17p deletion, 38%; 11q deletion, 13%; 13q deletion, 16%; trisomy 12, 21%; no findings, 12%; unmutated IgVH, 80%; ZAP70-positive, 75%; and CD38 ≥30%, 58%. Response in patients treated in the Phase II recommended dose is shown in Table (evaluable, 67). The overall response rates in patients with 17p and 11q deletions were 48% and 55%, respectively. The median survival duration was 21 months (CLL, 21 months; RS, 9.5 months). At 18 months, the survival rates in patients with 17p and 11q deletions were 66% and 76%, respectively. Twelve patients underwent stem cell transplantation after OFAR2 (as post-remission therapy, n=10; as salvage, n=2). Overall, 196 cycles were administered. Grade 3-4 neutropenia, thrombocytopenia, and anemia were noted in 63%, 72%, and 39% of patients and in 57%, 70%, and 25% of cycles and Grade 3-4 infections in 19% of patients. Conclusion Preliminary results demonstrated that OFAR2 induced response in 40% of patients with RS and 63% of patients with relapsed/refractory CLL. OFAR2 had antileukemic activity in patients with 17p deletion. Clinical outcomes appeared to be superior to those of OFAR1 in refractory CLL, whereas results of OFAR1 appeared to be superior to those of OFAR2 in RS. Accrual is ongoing. Disclosures Tsimberidou: ASCO: ASCO Career Development Award; Sanofi: Research Funding. Off Label Use: Oxaliplatin is used off-label. Wierda:Genentech: Honoraria; Bayer, Sanofi-Aventis, Abbott, GSK: Research Funding; GSK, Trubion, Ligand, Genentech, Medimmune, Abbot: Consultancy; Celgene: Speakers Bureau. Plunkett:Sanofi-Aventis: Research Funding. O'Brien:Genentech: Research Funding; Sanofi: Consultancy. Kipps:NCI: Grant P01CA-81534.

Final Report of a Phase I Study of Clofarabine Plus High Dose Melphalan as a Conditioning Regimen for Allogeneic Transplantation

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 528-528
Author(s):  
Mark Kirschbaum ◽  
Anthony Selwyn Stein ◽  
Paul Frankel ◽  
Leslie Popplewell ◽  
Robert w Chen ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Phase I ◽  
Dose Level ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Level 3 ◽  
Level 1 ◽  
Level 2 ◽  
Reduced Intensity

Abstract Abstract 528 Background: Allogeneic Stem Cell transplantation remains the only curative treatment modality for hematologic malignancies such as AML, ALL, and MDS. Reduced intensity regimens were designed which replaced the alkylating agent cyclophosphamide with the purine nucleoside antimetabolite, fludarabine, a potent immunosuppressive with a substantially milder toxicity profile. Clofarabine is a purine nucleoside analogue designed to exploit a double halogen strategy which confers resistance to adenosine deaminase, increases stability and bioavailability and makes the drug more efficient than fludarabine at inhibiting ribonucleotide reductase (RNR) and disrupting mitochondrial function, leading to apoptosis. Clofarabine is potentially a superior antileukemic agent as compared with fludarabine, thus enhancing the activity of the conditioning regimen. Aims: To evaluate a novel clofarabine containing regimen as conditioning for adult fully matched allogeneic stem cell transplant. Methods: phase I dose escalation: clofarabine (dose level 1 = 30 mg/m2, dose level 2 and 3 =40 mg/m2) IV daily days –7 to day –3 infused over 30 minutes IV, plus Melphalan (dose level 1 and 2, 100mg/m2, dose level 3, 140 mg/m2) administered over 30 minutes IV on day –2. Related or unrelated allogeneic stem cells were infused on day 0. GVHD prophylaxis: initially cyclosporine plus mycophenolate, then tacrolimus plus sirolimus was adopted as per City of Hope standard of care. Patients (pts) age ≥ 18 years with AML, ALL, MDS in either CR1, CR2 or in relapse (up to 50% marrow blasts), not deemed eligible for standard transplant regimens by the attending physician, or at high risk for relapse, are eligible. Results: 16 eligible pts, all with AML, have been treated thus far, 7,males, 9 females, with a median age of 63 years (30 – 66). Seven pts were in CR1, 2 pts were in CR2, 4 pts where induction failures, and 3 pts were in first relapse. Grade 3 non-hematologic toxicities included elevation of transaminases, diarrhea, and hyponatremia. No dose limiting toxicities (DLT) were seen in the 3 pts treated at dose level 1. One patient in dose level 2 died prior to engraftment due to hepatic, renal, and infectious toxicities; that dose level has been expanded to 12 patients and no further DLTs were seen. The first patient treated at dose level 3 developed multiorgan failure and died prior to engraftment. Given the excellent results seen in the two previous cohorts we opted not to dose escalate any further patients beyond clofarabine 40 mg/m2 and melphalan 100 mg/m2. Three patients with primary induction failure received an unrelated donor graft and had complete engraftment and obtained remission. The median time to ANC recovery is 14 days and to platelet recovery is 16 days (see table). Mild acute skin graft versus host disease (GvHD) was seen in five patients, mild chronic GvHD in four patients, one patient developed severe chronic GVHD of the liver and died at day 201 from CNS bleed due to tacrolimus-sirolimus related TTP-HUS. Of the 14 patients that successfully completed transplant (no DLT or engraftment difficulty), only one patient has relapsed, with median follow-up of 10.5 months (range 4–24). Conclusion: The combination of clofarabine and melphalan is a well tolerated reduced intensity conditioning regimen with enhanced anti-leukemia activity leading to complete engraftment of related and unrelated fully matched allogeneic stem cells. Complete engraftment with prolonged disease free survival was seen at both dose levels 1 and 2. Disclosures: Off Label Use: clofarabine as a component of the conditioning regimen for allogeneic transplant.

Cyclosporine Modulation of Multidrug Resistance in Combination with Pravastatin, Mitoxantrone, and Etoposide for Adult Patients with Relapsed/Refractory Acute Myeloid Leukemia (AML): A Phase 1/2 Study

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4343-4343
Author(s):  
Tara L Chen ◽  
Elihu H. Estey ◽  
Megan Othus ◽  
Kelda M. Gardner ◽  
Lauren Markle ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Multidrug Resistance ◽  
Dose Level ◽  
Phase 1 ◽  
Kidney Injury ◽  
Adult Patients ◽  
Hematologic Toxicity ◽  
Heavily Pretreated ◽  
Level 1 ◽  
Level 2

Abstract Abstract 4343 Background: Outcomes in relapsed/refractory AML are dismal. Given the high prevalence of multidrug resistance (MDR), many clinical studies have tested whether MDR reversal agents such as cyclosporine (CSA) could increase the efficacy of conventional chemotherapeutics but results have been inconsistent. More recently, HMG-CoA reductase inhibitors (e.g. pravastatin) have been investigated after demonstration that cholesterol synthesis inhibition can restore chemosensitivity of AML cells in vitro. As studies further suggested the HMG-CoA inhibitors could downregulate MDR function, we attempted to improve the efficacy of mitoxantrone and etoposide in patients with relapsed/persistent AML by combining CSA and pravastatin in a single-arm, open-label phase 1/2 trial. Patients and Methods: Adult patients with relapsed/refractory non-APL AML and a treatment-related mortality score of <9.2 (Walter et al. J Clin Oncol 2011) were eligible if they had an ECOG performance status (PS) ≤3 and adequate organ function. Prior hematopoietic cell transplantation (HCT) was permissible if relapse occurred >180 days post-HCT. Planned treatment included induction and consolidation therapy with pravastatin, CSA, and increasing doses of mitoxantrone and etoposide. All patients received pravastatin 320mg PO every 6 hours on days 1–10. The starting dose level (level 1) used etoposide 60mg/m2/day and mitoxantrone 5mg/m2/day via continuous infusion on days 5–9. CSA started 6 hours before the first doses of mitoxantrone/etoposide; after loading with 6mg/kg over 2 hours and 4mg/kg over 6 hours, CSA was infused at 18mg/kg/day on days 5–9. CSA levels were monitored on Day 6 and 8 to maintain levels <2,400ng/mL (by LCMS-MS). At dose level 2, identical doses of pravastatin and CSA were combined with etoposide (80mg/m2/day) and mitoxantrone (6mg/m2/day). Dose-limiting toxicities (DLTs) were defined as: 1) any Grade 3 non-hematologic toxicity lasting >48 hours except of febrile neutropenia (FN), infection, or hyperbilirubinemia; and 2) any Grade ≥4 non-hematologic toxicity except FN/infection, constitutional symptoms if recovery to Grade ≤2 within 14 days, and hyperbilirubinemia. An “adaptive” Bayesian phase 1–2 design that monitored both toxicity and response was used. The maximal acceptable rate of toxicity was 30%, the minimum acceptable rate of efficacy 20% (historical rate of 15% in this population), stopping when posterior probability >90%. A maximum of 45 patients would be treated in cohorts of 3. Results: Between October 2010 and February 2012, 10 patients (median age 52 [range 40–58] years) were treated, including 4 patients (all at dose level 1) who received therapy off protocol. Two patients had secondary AML, and 6 had complex cytogenetics. PS was 1 (7 patients) or 2 (3 patients). Average TRM score was 4.32 for on-study patients. All patients had received at least 2 prior regimens, and 7 received 3 prior therapies. One patient had undergone HCT. The average CSA level on Day 6 was 1,366.3ng/mL (range 713–2,082ng/mL) and 1,199.8ng/mL on Day 8 (range 526–1,593ng/mL). Efficacy (CR or CRi)/DLTs for on-study patients were: level 1 (n=3): 0/1 (grade 4 acute kidney injury); level 2 (n=3): 0/2 (grade 4 acute kidney injury; sepsis/multiorgan failure). Among the 7 patients treated at level 1, other toxicities included septic shock (n=1), FN (4), mucositis (2), and decreased left ventricular ejection fraction (1). One off-study patient achieved CR after 1 course and received 1 cycle of consolidation with pravastatin, etoposide, and mitoxantrone but experienced CNS relapse after CR duration of only 46 days. Based on the results of the on-study patients, the statistical monitoring mandated early study closure for lack of efficacy & excessive toxicity. Conclusion: In the targeted, heavily pretreated patient population, the study regimen was excessively toxic and failed to achieve acceptable efficacy. Further clinical testing, if any, should be limited to less heavily pretreated, otherwise “fit” patients with AML. This trial was registered at ClinicalTrials.gov as NCT01342887. Disclosures: No relevant conflicts of interest to declare.

Phase 1 Dose-Escalation Study of 90yttrium-Labeled Anti-CD22 Epratuzumab Tetraxetan in Adults with Refractory/Relapsed CD22+ B-Cell Acute Lymphoblastic Leukemia (B-ALL)

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3708-3708
Author(s):  
Patrice Chevallier ◽  
Thomas Eugene ◽  
Nelly Robillard ◽  
Françoise Isnard ◽  
Franck E Nicolini ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Lymphoblastic Leukemia ◽  
Lymphoblastic Leukemia ◽  
Phase 1 ◽  
Whole Body ◽  
Organ Distribution ◽  
Hematologic Toxicity ◽  
Level 3 ◽  
Level 1 ◽  
Level 2

Abstract Background: Prognosis of relapsed/refractory acute lymphoblastic leukemia (ALL) in adults is dismal. CD22 is highly expressed in patients with B-ALL. Epratuzumab (hLL2) is a humanized monoclonal antibody targeting CD22 surface antigen. We performed a standard 3+3 phase 1 study to assess the feasibility, tolerability, and efficacy of a 90yttrium-labeled anti-CD22 epratuzumab tetraxetan (90Y-DOTA-hLL2) radioimmunotherapy (RIT) in adults with refractory/relapsed CD22+ B-ALL. Methods: After premedication with corticosteroid, 90Y-DOTA-hLL2 was administered twice on days 1 and 8 (+2), successively at 2.5 (level 1), 5.0 (level 2), 7.5 (level 3), and 10.0 (level 4) mCi/m². The first two patients also received 4 infusions of DOTA-hLL2 360 mg/m²/day before the RIT. This “cold phase” was terminated after observing no efficacy and full saturation of the CD22 target on the leukemic cells. Minimal residual disease (MRD) was assessed either by flow cytometry or by RQ-PCR for BCR-ABL1 analyses in Philadelphia chromosome positive (Ph+) B-ALL patients. Dose-limiting toxicity (DLT) was defined as any non-reversible grade >3 non-hematological toxicity or grade 4 pancytopenia with hypocellular bone marrow lasting for >6 weeks. Maximum tolerated dose (MTD) was defined as the dose level at which 2 of 3 or 2 of 6 patients experienced a DLT. Dosimetry, organ distribution and elimination of the radiotracer were studied between the two RIT infusions in all but one patient, using whole-body scintigraphy recorded after 111Indium-epratuzumab tetraxetan injection and blood pharmacokinetics. Patients were evaluated for response between 4 and 6 weeks following the first infusion of RIT. Findings: Between October 2011 and June 2014, 20 patients were enrolled. Three patients were not considered for analyses because of disease progression (n=2) or persistent non-blastic pancytopenia (n=1) before RIT. Overall, 17 cases were treated (5 at level 1 including 2 previously treated with the cold phase, 3 at level 2, 3 at level 3, and 6 at level 4). There were 10 males and 7 females with a median age of 62 years (range: 27-77). Two patients had primary refractory B-ALL; 10, 3 and 2 were in first, second or third relapse, respectively. Median percentage of blasts in the bone marrow was 75%. Karyotypes were as follows: Ph+ B-ALL n=6, complex n=3, MLL rearrangement n=1, hyperdiploidy n=1, hypodiploidy n=1, near-triploidy n=1, del4q (+ikaros mutation) n=1, normal (but ikaros mutation) n=1, and unknown n=2. Four patients were previously allotransplanted. Median interval between diagnosis and RIT was 16.5 months. Five patients presented immediate infusion reactions (3 grade 1, 1 grade 2 and 1 grade 3 in a patient with a previous history of severe allergic reactions) after the first RIT infusion, but received the second infusions without toxicities. All examined patients showed expected uptake of the radiotracer on potential disease sites (blood, spleen, liver, and bone marrow). No response was seen at levels 1 and 3. One molecular complete response was documented at level 2 (54-year old woman in third relapse of Ph+ B-ALL). At level 4, 2 patients achieved complete remissions (1 Ph+ ALL and 1 Ph- ALL), while all 6 cases presented with grade 4 hematologic toxicity. One DLT was documented at level 4 (non-blastic pancytopenia lasting 8 weeks), but MTD was not reached. Two patients in response received a second RIT cycle. Currently, only one non-responder is alive, while 2 of 3 responders are alive. One relapsed at 1 year and died of progression (level 2), while the two remaining are in persistent CR at 6 months post RIT, with low positive MRD. Interpretation: 90Y-DOTA-hLL2 RIT is well-tolerated and induced complete remissions even in heavily pre-treated CD22+ relapsed/refractory B-ALL patients, thus appearing to be a promising targeted therapy for CD22+ B-ALL. We recommend the dose of 10 mCi/m² given twice, one week apart/cycle, for phase 2 studies. The trial is registered at http://clinicaltrials.gov/ct no.NCT01354457. Funding: Immunomedics, Inc. Disclosures Goldenberg: immunomedics: Employment. Wegener:immunomedics: Employment.

Docetaxel and capecitabine for previously treated metastatic colorectal cancer

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 13579-13579
Author(s):  
T. E. O’Brien ◽  
E. Newton ◽  
J. Trey ◽  
E. Crum
Keyword(s):  
Colorectal Cancer ◽  
Phase I ◽  
Dose Level ◽  
Low Dose ◽  
Metastatic Breast ◽  
Human Colon Cancer ◽  
Level 3 ◽  
Previously Treated ◽  
Level 1 ◽  
Level 2

13579 Background: Docetaxel (D) induces human colon cancer cell lines to upregulate thymidine phosphorylase, an enzyme which activates capecitabine (C) to its cytotoxic form. This provided rationale for adding low dose D to C in patients with colorectal cancer (CRC). Although this combination has been established in metastatic breast cancer, it has not been evaluated in CRC. Because of concerns of toxicity in a pretreated population, we performed a phase I trial in patients with previously treated CRC. Methods: Eligibility: At least 1 prior treatment for metastatic disease; ECOG PS 0–1; adequate organ function. Design: Phase I, dose escalation. D, IV, days 1 & 8, and C, PO BID days 5–18, repeated q21days. Dose Level 1: D=15mg/m2, C=1000mg/m2; Level 2: D= 15 mg/m2, C= 1100 mg/m2; Level 3: D= 20 mg/m2, C= 1100 mg/m2; Level 4: D=20mg/m2, C=1250mg/m2. Results: 13 patients have thus far been treated. 11 are evaluable for toxicity and 10 for response (1 at dose level 4 was taken off study due to non-compliance before completion of cycle 1; another died of progressive cancer before completing cycle 1 at dose level 4; another is evaluable for toxicity but not yet for response). 9 with colon, 4 with rectal primary sites. Median follow-up= 5 mo (1–19 mo). Med age= 59 (30–75); #prior regimens for met disease 1–2, all of which were 5-FU based. Toxicities No dose limiting toxicities (DLT) until Dose Level 4. Dose Level 1: 1/3 developed grade 2 diarrhea and hand-foot syndrome and delayed grade 3 hand-foot; Dose Level 2: 2/3 developed grade 2 toxicities (hand-foot in one and diarrhea in the other); Dose Level 3: 1/3 developed delayed grade 2 hand-foot; Dose Level 4: 1 patient with delayed grade 2 hand-foot and grade 1 eye tearing; another developed DLT (grade 4 stomatitis/dehydration). Response 6/10 patients progressed after 2 cycles; 2 pts had stable disease, one lasting 4.6 mo; 2 patients had a partial response, one of which lasted 9 mo. The latter case had refractory disease to FOLFOX 4 but a 78% reduction in her liver metastases to D+C. Conclusions: The combination of low dose docetaxel, used as chemosensitizing agent, with capecitabine in this pretreated group of patients with metastatic CRC appears to be well tolerated, with no DLTs seen until Dose Level 4, and has modest activity. MTD determination awaits further accrual. No significant financial relationships to disclose.

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