Phase I Study of Triapine® and Cytarabine (ara-C) in Patients with Relapsed or Refractory Acute Leukemias and High-Risk Myelodysplastic Syndrome (MDS).

Abstract Triapine is a potent inhibitor of ribonucleotide reductase (RNR), which is required for the conversion of ribonucleotides to deoxyribonucleotides. Two phase I trials in patients with hematologic malignancies demonstrated that Triapine could reduce circulating blasts in the majority of patients without significant non-hematologic toxicity (Giles et al. Leuk Res2003;27:1077–1083; Karp et al. Blood2002;100:560a). Preclinical studies have shown that the combination of Triapine and ara-C produces additive or synergistic cytotoxicity against several tumor cell lines, potentially by increasing intracellular ara-CTP levels when Triapine inhibits RNR. Therefore, a phase I study of Triapine in combination with ara-C was conducted in 32 patients with relapsed or refractory acute leukemia and high-risk MDS (1 MDS, 28 AML, 2 Ph+ ALL, and 1 Ph- ALL) in order to determine the tolerability, safety, and maximum tolerated dose (MTD). Triapine® was administered at a dose of 105 mg/m2/d as a 6-hour infusion for 5 consecutive days (D1–5) followed immediately by ara-C [100 (n=4), 200 (n=6), 400 (n=7), or 800 (n=8) mg/m2/d] as an 18-hour infusion for 5 consecutive days (D1–5). Median age was 59 years (range, 15–83 years). Median ECOG status 1 (range, 0–2). Median number of prior therapies was 2 (range 1–9), including prior autologous (n= 2) and allogeneic stem cell transplant (SCT) (n=4). Dose-limiting toxicities (DLTs) were observed at the 800 mg/m2 ara-C dose level (1 patient each with grade 4 mucositis; grade 4 neutropenic colitis, sepsis and death; grade 4 neuropathy; and grade 4 hyperbilirubinemia). Therefore, the study was amended to include an ara-C dose level of 600 mg/m2/d. Seven patients were treated at this dose level without development DLTs. Thirty-one patients received at least 1 course, 2 received 2 courses, and 4 received 3 courses; 1 patient withdrew prior to completion of 1 course of therapy. Of the 31 evaluable patients, 4 (13%) patients (3 AML, 1 Ph+ ALL) achieved a CR (1 at an ara-C dose of 800 mg/m2; 2 at 600 mg/m2; 1 at 200 mg/m2). Two of the responders also achieved a complete cytogenetic remission (including 1 Ph+ ALL). All responses occurred after 1 induction course. One patient went on to receive an allogeneic (SCT) and continues in CR. Duration of responses was 9, 20, 52+, and 73+ weeks. Mean Cmax and AUC achieved for Triapine were 1.13 μg/mL and 251.5 min•μg/mL. The most frequent toxicities included nausea &/or vomiting (66%), elevated liver enzymes (50%; gr. 3 in 22%), fever (47%), diarrhea (41%; gr. 3 in 6%), rash (31%; gr. 3 in 6%), mucositis (28%), hand-foot syndrome (16%; gr. 3 in 3%), and peripheral edema (16%; gr. 3 in 9%). Triapine and cytarabine has activity in patients with relapsed or refractory acute leukemias. The recommended phase II dose is Triapine 105 mg/m2/day for 5 consecutive days (D1–5) followed by ara-C 600 mg/m2/d for 5 consecutive days (D1–5).

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Phase I Study of Clofarabine Plus Idarubicin and Clofarabine Plus Idarubicin Plus Cytarabine (ARA-C) in Patients (PTS) with Relapsed and Primary Refractory Acute Myeloid Leukemia (AML), Myelodysplastic Syndrome (MDS), and Myeloid Blast Phase of Chronic Myeloid Leukemia (CML).

Blood ◽

10.1182/blood.v104.11.1809.1809 ◽

2004 ◽

Vol 104 (11) ◽

pp. 1809-1809 ◽

Cited By ~ 1

Author(s):

Stefan Faderl ◽

Alessandra Ferrajolil ◽

William Wierda ◽

Srdan Verstovsek ◽

Farhad Ravandi-Kashani ◽

...

Keyword(s):

Phase I ◽

Dose Level ◽

Myeloid Leukemia ◽

Phase I Study ◽

Maximum Tolerated Dose ◽

Clinical Activity ◽

Acute Leukemias ◽

First Remission ◽

First Relapse ◽

Grade 3

Abstract Phase I and II clinical studies demonstrated activity of Clofarabine in acute leukemias. In previous studies we have investigated clofarabine, plus ara-C combinations and reported a CR rate of 24% in relapsed AML and 52% in previously untreated AML ≥ 50 years (yrs) with acceptable toxicity profile. Anthracyclines are active in AML. To explore clofarabine further in AML combinations we conducted a phase I study of clofarabine with idarubicin with or without ara-C in pts with relapsed AML, MDS, and CML. Considered as dose-limiting toxicities (DLT) are ≥ grade 3 drug-related toxicities. Maximum tolerated dose (MTD) will be determined by “3+3” dose escalation scheme. On the clofarabine (C)/idarubicin (I) combination (CI), 9 AML pts are enrolled (2 primary refractory, 7 first relapse). Median age: 58 yrs (range 24–71). Median first remission duration (CRD1): 3.1 mos. (0–7.6). For the first dose level, C was given at 22.5mg/m2 i.v. daily x 5d and I at 12mg/m2 i.v. daily x 3d. Among the first 6 pts, 2 ≥ gr. 3 toxicities (diarrhea, rash, ↑ bili) occurred necessitating dose de-escalation of C to 15mg/m2 i.v. daily x 5 and I 8mg/m2 i.v. daily x 3. Among 3 pts, 1 ≥ gr.3 toxicity (↑ bili) was observed. No responses occurred. On the CI + ara-C arm (CIA), 7 AML pts are enrolled (1 primary refractory, 6 first relapse). Median age: 58 yrs. (24–78). Median CRD1: 11.2 mos. (0–13.1). First dose level: C 22.5mg/m2 i.v. daily x 5d, I 8mg/m2 i.v. daily x 3d, A 1g/m2 i.v. daily x 5d. Of 3 pts, 2 developed ≥ gr.3 toxicities (↑ bili, diarrhea) leading to the following de-escalation: C 15mg/m2 i.v. daily x 5d, I 6mg/m2 i.v. daily x 3d, A 0.75g/m2 i.v. daily x 5d. Of 4 pts (1 ≥ gr. 3 rash, ↑ bili), 3 pts achieved CR. The phase I study is ongoing until determination of DLT and MTD for each arm. Our preliminary results indicate clinical activity of CIA even at the low dose level.

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A Phase I-II Dose Escalation Trial of Clofarabine Plus Melphalan and Thiotepa Followed by Unmodified Allogeneic Stem Cell Transplant (SCT) for the Treatment of High Risk or Advanced Acute Leukemia

Blood ◽

10.1182/blood.v116.21.2354.2354 ◽

2010 ◽

Vol 116 (21) ◽

pp. 2354-2354

Author(s):

Farid Boulad ◽

Nancy A Kernan ◽

Susan E Prockop ◽

Andromachi Scaradavou ◽

Trudy N Small ◽

...

Keyword(s):

Stem Cell ◽

High Risk ◽

Phase I ◽

Dose Level ◽

Unrelated Donor ◽

Cell Transplant ◽

Acute Leukemias ◽

Unrelated Donors ◽

Disease Free

Abstract Abstract 2354 High-risk or advanced acute leukemias are associated with poor outcome even with the use of stem cell transplantation (SCT) with or without total body irradiation (TBI). Based on encouraging results with the use of clofarabine (CLO) for reinduction treatment of acute leukemias, we have developed a phase I/II protocol using this agent with melphalan (Mel) and thiotepa (Thio) followed by unmodified SCT for the treatment of patients (pts) with high-risk (HR) leukemias. To date, 28 consecutive pts were treated on, or as per protocol, with 26 pts evaluable for follow-up. There were 15 males and 11 females aged 1–58 years (median 5.3 years). Cytoreduction consisted of CLO at dose level I of 20 mg/m2/day × 5 days (n=23) or at dose level II of 30 mg/m2/day × 5 (n=3), Thio 10 mg/Kg/day × 1 day and Mel 70 mg/m2/day × 2 days. Graft-versus-host disease (GvHD) prophylaxis consisted of tacrolimus and mycophenolate mofetil (MMF), or tacrolimus and methotrexate. Twenty pts had acute lymphoblastic leukemia (ALL) in complete remission (CR1; n=5), CR2 (n=5), CR3 (n=9), or relapse (n=1). Five pts had acute myeloid leukemia (AML), in CR1 (n=1), CR2 (n=2), or CR3 (n=2). One pt had myelodysplastic syndrome (MDS) in RAEB. For the pts with ALL in CR1, very HR features included: Infant MLL (N=2), Philadelphia (Ph1) chromosome (N=2) and Induction failure (N=1). For the pts with ALL in CR2, HR features included: Infant MLL (N=1), 2nd SCT (N=1), Ph1 and 2nd SCT (N=2), while 1 pt had prior CNS infarcts precluding the use of TBI. The one pt with AML in CR1 had M7-AML. This was a first SCT for 14 pts, a 2nd SCT for 11 pts and 3rd SCT for 1 pt, with time from previous SCT to the present one being 5–73 months (median 11.3 mo) for those 12 pts. Donors were HLA-matched siblings (n=8), HLA matched unrelated donors (n=8), or HLA mismatched unrelated donors (N=10). Stem cell grafts were bone marrow (n=12), peripheral blood (n=7) or double cord blood (n=7) stem cells. Twenty four of the 26 evaluable pts engrafted, while 2 pts died prior to engraftment. Toxicity of the SCT cytoreduction included elevation of hepatic transaminases in 17 of 26 evaluable pts (AST elevation of 5–19 fold and ALT elevation of 7–16 fold), with a subsequent normalization in all pts. Mucositis was mostly at acceptable grade 1–2 levels. Two pts developed a syndrome of renal and hepatic insufficiency leading to hepatic veno-occlusive disease (VOD) (1 pt at each of the 2 dose levels). Non-relapse mortality included: VOD (N=2), infections (N=3), treatment related sarcoma, a malignancy secondary to the irradiation received with a prior transplant (N=1). With a follow-up of 3–57 mos (median 21 mos), 15 of the 26 pts are alive, disease-free. Five pts relapsed and 4 died subsequently of disease, while 6 pts died of non-relapse morality. Overall (OS) and disease-free survival (DFS) at 2 years were both 58%. DFS was 56% for pts > 18 years and 53% for pts < 18 years (p =0.36); it was 64% for recipients of a first HSCT and 41% (p=0.97) for recipients of a second or third HSCT. Five pts (4 recipients of unrelated donor SCT; 3 from mismatched donors) developed Grade 2–4 acute GvHD. Four of these pts went on to develop chronic GvHD. Immune reconstitution was rapid; for the evaluable pts, it included absolute CD4 counts > 200 cells/L at 1–3 mos for 15 pts and at 4–8 mos for 4 pts. This cytoreductive regimen represents a promising approach for the transplantation of patients with high risk acute leukemias. It was well tolerated for pts requiring a second SCT and is also associated with rapid immune recovery. Ultimately, a large scale study would need to be done to determine if this approach could offer equal or superior results to TBI containing regimens for ALL or AML. Disclosures: No relevant conflicts of interest to declare.

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V2 Trial: A phase I study of venetoclax and CPX-351 for young patients with relapsed/refractory acute leukemia.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.tps7052 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. TPS7052-TPS7052

Author(s):

Laura Agresta ◽

Maureen Megan O'Brien ◽

Eric Justin O'Brien ◽

Robin Elizabeth Norris ◽

Erin Haag Breese ◽

...

Keyword(s):

Acute Leukemia ◽

Phase I ◽

Dose Level ◽

Phase I Study ◽

Bone Marrow Failure ◽

Young Patients ◽

Cell Transplant ◽

Acute Leukemias ◽

Hematopoietic Stem ◽

Level 1

TPS7052 Background: Despite significant advances in therapy for acute myeloid leukemia (AML), 30-40% of young patients will relapse, after which prognosis is poor. In young patients, curative-intent salvage therapy involves intensive re-induction followed by hematopoietic stem cell transplant. Recently, the COG Phase II study of CPX-351 (liposomal cytarabine:daunorubicin, Vyxeos™) in pediatric patients with AML in first relapse (NCT02642965) demonstrated a CR/CRi rate of 81.3%. Separately, our first-in-pediatrics CPX-351 Phase I (NCT01943682) showed 48% in a heavily pre-treated pediatric cohort with multiply relapsed and refractory (R/R) AML. Our integrated pilot study of single cell RNA sequencing (scRNA-seq) done before, during, and after CPX-351 showed p53 targets over time with enrichment for genes regulating apoptosis (ex.: FAS, BAX), suggesting blasts may be primed for apoptosis following CPX-351. Venetoclax is a small molecule inhibitor of the anti-apoptotic protein BCL-2, a regulator of apoptotic balance in some leukemias. Based on our preclinical data, we developed a Phase I study to investigate venetoclax with CPX-351 for the treatment of young patients with R/R acute leukemias. Methods: The V2 Trial (NCT03826992) is a single-institution Phase I study to evaluate the safety and tolerability of venetoclax with CPX-351 in patients ages 1-39 years with R/R acute leukemias. Inclusion diagnoses include AML, mixed phenotype acute leukemia (MPAL), KMT2A-rearranged acute lymphoblastic leukemia (ALL), and T-ALL. Exclusion criteria include CNS status 3, bone marrow failure syndromes, and prior cardiotoxic exposures above acceptable risk thresholds. Subjects receive a single course of CPX-351 at the FDA approved adult dose on Days 1, 3, 5 with concurrent daily venetoclax. In the dose exploration phase, venetoclax dosing is 400 mg daily (or allometrically-scaled equivalent) for 21 (Dose Level 0) or 14 days (Dose Level -1) using a rolling 6 design. Primary endpoints are determination of the recommended phase 2 dose of venetoclax in combination with CPX-351 and description of toxicities. Secondary endpoints include estimations of CR/CRp/CRi +/- MRD negativity in the context of a phase I study and evaluation of therapy-related cardiac dysfunction. Correlative studies include analysis of venetoclax pharmacokinetics with concomitant CPX-351. At the initial dose level, DLT were encountered and the study is now continuing enrollment at Dose Level -1. Clinical trial information: NCT03826992.

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A Safety Study of the Addition of Omacetaxine to the Standard-of-Care Induction Regimen of Cytarabine and Idarubicin in Newly-Diagnosed AML Patients

Blood ◽

10.1182/blood-2018-99-111412 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 5218-5218

Author(s):

Sonia Christian ◽

Kelley E. Kozma ◽

Stephanie Barath ◽

Ardaman Shergill ◽

Damiano Rondelli ◽

...

Keyword(s):

High Risk ◽

Phase I ◽

Dose Level ◽

Dose Escalation ◽

De Novo ◽

Standard Of Care ◽

Hematologic Toxicity ◽

Newly Diagnosed ◽

Induction Regimen ◽

Dose Levels

Abstract Background: Omacetaxine mepesuccinate (OM) is a semi-synthetic form of Homoharringtonine (HH), a cephalotaxine alkaloid. OM induces cell apoptosis by inhibiting peptide bond formation during mRNA translation, with rapid loss of short-lived proteins, such as MCL-1, c-MYC, and Cyclin D1 (Lu, J Hematol Oncol. 2014, 7: 2). Notably, cytarabine synergizes with HH in causing apoptosis of leukemia cells in vitro. A phase III RCT in China of 620 patients with de novo AML demonstrated superior CR and 3-yr survival rates upon addition of HH to a standard 2-drug AML induction therapy ('7 + 3'; Jin, Lancet Oncol. 2013, 14:599). Thus, we hypothesized that OM, at an appropriate dose, would similarly enhance the efficacy of a 7 + 3 regimen. OM is FDA-approved for the treatment of TKI-resistant CML. The MTD of 1.25 mg/m2/d SQ for 14 days every 28 days, as determined in a phase I/II CML trial of OM (Quintás-Cardama, Cancer 2007, 109: 248), served as a basis for the dose escalation used in this study. Methods: The primary endpoint of this phase I safety trial was to determine the optimally safe and active dose (OD) of OM when added to a standard 7 + 3 induction regimen, cytarabine and idarubicin. OM was administered SQ q12h d1-7 with cytarabine (100mg/m2 CIV) d1-7 and idarubicin (12mg/m2 IV) d1-3. Four dose levels were tested, starting with OM 0.625 mg/m2 q12h (further dose levels: 1.25, 2.0, 3.0, and 4.2 mg/m2 q12h). All newly diagnosed, untreated de novo or secondary AML patients, aged 18-70y with ECOG PS of 0-3 were eligible for this study. Secondary endpoints included overall response rate (ORR) and overall and event free survival (OS, EFS). Hematologic toxicity (HT) was defined as incomplete hematologic recovery; ANC < 1.0 x 109/L or platelet count < 100 x 109/L present at d49, with the bone marrow documented to be free of leukemic infiltration. Dose escalation was based on the EffTox design (Biometrics 2004, 60:684), a Bayesian adaptive design which considers the trade-off between efficacy and toxicity in determining the OD for Phase II trials. Results: Twenty-two patients, median age 58 (range 25-69) years were enrolled from June 2015 to June 2018. 12 patients (54.5%) had adverse cytogenetics, 6 (27%) intermediate risk, 3 (13.7%) favorable risk and 1 patient's cytogenetic risk was unknown (fibrotic BM). Eight patients demonstrated disease evolution from myelodysplastic syndrome (MDS). Altogether 16 of the 22 patients (73%) were deemed high risk based on cytogenetics or MDS-AML evolution. The EffTox design was implemented until cohort 4 (3 mg/m2 q12h), where 2 of 3 patients experienced a grade 5 non-hematologic toxicity (NHT), resulting in a dose-limiting toxicity (DLT). Since no DLTs were observed in cohort 3, an additional 5 patients were thus enrolled at this dose level to ensure safety. The OD was determined to be the dose level used in cohort 3: OM 2 mg/m2. No HTs were observed in 21 of 22 patients, (one patient not evaluable). The most common non-hematologic treatment emergent adverse events (TEAEs) of any grade were fever (68%), nausea (64%), vomiting (55%), hyperglycemia (41%), diarrhea (41%), mucositis (36%), headache (36%), sinus tachycardia (32%), rash/dermatitis (32%), and abdominal pain (32%). The most prevalent non-hematologic grade 3/4 TEAEs were febrile neutropenia (23%), hypoxia (18%), hyperglycemia (18%), and dyspnea (18%). ORR (CR and CRi) was 45.5%. Median OS was 605 days and EFS was 100 days. Conclusion: In this population with predominantly high-risk AML, the combination of OM with a standard 7 + 3 regimen demonstrates a manageable safety profile with acceptable efficacy. As ~ 25% of patients achieving CR with '7 + 3' do so after a second induction (based on meta-analysis of 6 trials, n = 1980, see Cancer 2010, 116: 5012), the ORR here is comparable to those receiving a single standard of care induction. The results in this high-risk group are therefore promising and warrant further investigation in a phase II trial. At present, we are assessing leukemic blast MCL protein expression in stored pre-treatment samples to determine if this predicts OM efficacy. NCT02440568. Teva has performed a Medical Accuracy Review of this abstract. Figure. Figure. Disclosures Khan: Teva: Speakers Bureau. Patel:Celgene: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Janssen: Honoraria.

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A Phase I–II Trial of Bortezomib (Velcade) (Vc) and Oral Cyclophosphamide (CY) Plus Prednisone (P) for Relapsed/Refractory Multiple Myeloma (MM).

Blood ◽

10.1182/blood.v106.11.2556.2556 ◽

2005 ◽

Vol 106 (11) ◽

pp. 2556-2556 ◽

Cited By ~ 8

Author(s):

Donna E. Reece ◽

Giovanni Piza ◽

Suzanne Trudel ◽

Christine Chen ◽

Joseph R. Mikhael ◽

...

Keyword(s):

Phase I ◽

Dose Level ◽

Progression Free Survival ◽

Maximum Tolerated Dose ◽

Hematologic Toxicity ◽

Combination Regimen ◽

Free Survival ◽

Best Response ◽

Level 3 ◽

Ongoing Phase

Abstract We have previously reported that a simple, well-tolerated regimen of weekly oral CY (500mg) and alternate day prednisone (50–100mg) produced partial responses (PR) in 40% of 56 patients (pts) in relapse after ASCT; median progression-free survival was 18.6 months (Blood2004; 104[11]: 311b). To build upon these favorable results, we have designed an ongoing phase I–II trial adding Vc to this regimen. CY was given p.o. once weekly on days 1,8,15 and 22 of each 28 day cycle while prednisone was given every other morning. CY was given before Vc on appropriate days. A maximum of 8 cycles was administered. Sixteen pts have been entered so far. Patients characteristics: Median age was 59 (48–74) years; 9 were male. The Ig subtypes were: IgG kappa:lambda = 9:2, IgA kappa:lambda = 1:2; kappa light chain = 2. All had received VAD, i.v. CY (2.5 g/m2) + G-CSF mobilization followed by ASCT and 2 had undergone a second ASCT; other prior regimens included melphalan and prednisone in 5 pts, thalidomide in 10, lenalidomide in 1, α-interferon in 3, vaccine therapy in 1 and oral CY + P in 8. The median pretreament ß2-microglobulin level was 279 (147 – 875) nm/L, albumin 39 (30–42) g/L and creatinine 91 (60–112) umol/L. The dose escalation schedule to date is as follows: Dose Level N P dose CY dose (mg/m2) Vc dose (mg/m2) 1 6 100 150 0.7 d 1,8,15 2 3 100 300 0.7 d 1,8,15 3 3 100 300 1.0 d 1,8,15 4 4 100 300 1.0 d 1,4,8,11 Three further dose escalations to a maximum Vc dose of 1.5 mg/m2 days 1,8, and 15 are allowed if dose limiting toxicity does not occur. Toxicities during cycle 1: All pts have completed cycle 1. Three episodes of grade (gr) 3 sinopulmonary infection occurred during a community outbreak at dose level 1; levofloxacin prophylaxis during the first cycle was added and no further infections during the initial cycle were observed. One pt at dose level 3 experienced transient gr 4 hypophosphatemia which reversed without therapy. At dose level 4, cycle 1 was interrupted in one pt due to gr 4 leukopenia (gr 3 neutropenia and thrombocytopenia) related to disease, while a second pt developed grade 4 elevation in transaminases which recovered quickly when Vc was held on d 8. Pt accrual continues. Toxicities of subsequent cycles: To date, 47 additional cycles have been given. SAE’s consisted of pneumonia during cycle 2 in the same 3 patients with infection during cycle 1 and one of these with progressive disease had another bout during cycle 3. Gr 3 toxicities included anemia in 2 cycles, leucopenia in 2, neutropenia in 4, hypophosphatemia in 1 and hyperglycemia in 2; reversible gr 4 hypophosphatemia recurred in the pt mentioned above in 1 other cycle. No liver or other organ toxicity was observed. Maximum gr of peripheral neuropathy was 1. Responses: Responses were assessed after cycles 2, 4, 6 and 8. Best response included near CR (1), PR (4), MR (4), stable disease (5), progression (1) and too early (1). Two pts have completed all 8 cycles, while 4 have progressed; 10 remain on study. Preliminary Conclusions: 1) Vc can be added to a continuous program of oral CY + P with acceptable hematologic toxicity; 2) no neurotoxicity > gr 1 has been observed; 3) the maximum tolerated dose (MTD) of this combination regimen has not yet been defined; 4) future plans include a randomized National Cancer Institute of Canada trial comparing the the MTD of this combination to Vc in relpased MM pts.

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A Phase I/II Trial on Melphalan, Prednisone, Thalidomide and Defribotide Combination in Relapsed/Refractory Multiple Myeloma Patients.

Blood ◽

10.1182/blood.v110.11.2715.2715 ◽

2007 ◽

Vol 110 (11) ◽

pp. 2715-2715

Author(s):

Antonio Palumbo ◽

Alessandra Larocca ◽

Cecilia Rus ◽

Francesca Gay ◽

Davide Rossi ◽

...

Keyword(s):

Multiple Myeloma ◽

Phase I ◽

Dose Level ◽

Bleeding Risk ◽

Maximum Tolerated Dose ◽

Protective Role ◽

Pharmacokinetic Studies ◽

Hematologic Toxicity ◽

Vein Thrombosis ◽

Deep Vein

Abstract Defibrotide (DF) showed antithrombotic properties and remarkable activity in Multiple Myeloma (MM), without significant anticoagulant effects and bleeding risk. DF may abrogate tumor cells interaction with marrow stromal cells and enhance sensitivity to chemotherapy, thus improving activities of Melphalan, Prednisone and Thalidomide, while protecting against thrombotic state. We designed a multicenter phase I/II trial to define efficacy and safety of Melphalan, Prednisone, Thalidomide and DF (MPTD) in relapsed/refractory MM. The MPTD treatment consisted of 6 35-days cycles of oral melphalan (0.25 mg/Kg day 1–4), prednisone (1.5 mg/kg day 1–4), thalidomide (50–100 mg/day continuously), DF at 3 dose levels (17 mg/Kg iv or 2.4 g po D 1–4, 1.6 g po D 5–35; 34 mg/Kg iv or 4.8 g po D 1–4, 3.2 g po D 5–35; 51 mg/Kg iv or 7.2 g po D 1–4, 4.8 g po D 5–35), every 35 days, without deep vein thrombosis (DVT) prophylaxis. Safety was assessed by defining dose-limiting toxicity (DLT) and maximum tolerated dose (MTD). DLT was defined as the occurrence of febrile neutropenia, G4 neutropenia >1 week, any other G4 hematologic toxicity, or any >G3 non-hematologic toxicity. MTD was the dose level prior to that resulting in DLT. Efficacy was evaluated according to EBMT/IBMTR criteria. Twenty-four patients were enrolled between March and November 2006 and 19 patients completed at least 1 MPTD (median age 69, excluding primary refractory and/or patients receiving anticoagulation) and were evaluated for toxicity and response. Fourty-two percent of patients achieved at least partial response (PR) after a median of 3 cycles (including 16% very good PR), without significant differences among DF dose. The MTD was not reached. DLTs observed were not considered related to DF and included: G3 ileus (1st dose level) and acute myocardial infarction (AMI) in the 2nd. Toxicities ≥G3 consisted of neutropenia 47%, thrombocytopenia 10%, anemia 21%, whereas <5% of patients experienced non-hematological toxicities ≥G3. No DVTs or significant bleeding were detected. Treatment discontinuation occurred in 3 patients for adverse events: AMI (additional anticoagulation required), ileus (because of the diagnosis of amyloidosis AL and disease progression), and persistent G4 neutropenia (heavily pre-treated patients). In this phase I/II study we confirm the efficacy and feasibility of MPTD in the setting of advanced myeloma patients, interestingly a protective role of DF against thrombosis is also suggested. Pharmacokinetic studies and analysis of surrogates are ongoing. Updated data will be presented at the meeting.

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A Phase I Trial of Two Sequence-Specific Schedules of Decitabine and Vorinostat in Patients with Acute Myeloid Leukemia (AML).

Blood ◽

10.1182/blood.v110.11.908.908 ◽

2007 ◽

Vol 110 (11) ◽

pp. 908-908 ◽

Cited By ~ 2

Author(s):

Karen W.L. Yee ◽

Mark D. Minden ◽

Joseph Brandwein ◽

Aaron Schimmer ◽

Andre Schuh ◽

...

Keyword(s):

Phase I ◽

Dose Level ◽

Phase I Trial ◽

Concurrent Schedule ◽

Maximum Tolerated Dose ◽

Leukemic Cells ◽

Clinical Activity ◽

Cell Transplant ◽

Sequential Schedule ◽

Grade 3

Abstract Background: Epigenetic silencing of genes has been documented in AML. This phase I trial evaluates the safety, tolerability, and maximum tolerated dose (MTD) of two schedules of administration of the hypomethylating agent decitabine in combination with the pan-selective histone deacetylase inhibitor vorinostat. Methods: Patients receive escalating doses of oral vorinostat administered either sequentially [100 mg bid (n=4), 200 mg bid (n=4), or 200 mg tid (n=8) Days 6–21] or concurrently [100 mg (n=3) or 200 mg (n=6) bid Days 1–21 or 200 mg tid (n=2) Days 1–14] with decitabine (20 mg/m2/d IV Days 1–5) every 28 days. Results: Twenty-seven patients with AML have been treated. Median age was 67 years (range, 32–82 years). Median ECOG status 1 (range, 0 to 2). Eighteen patients (67%) had received prior therapy (median, 1 regimen; range, 0 to 4 regimens); 3 had received a prior allogeneic stem cell transplant. A total of 85 cycles have been administered, with a median of 2 cycles (range, 1 to 13 cycles); 10 patients (37%) have received 3 or more cycles of therapy. One of 7 patients treated at dose level 3 of the sequential schedule developed dose-limiting toxicities (DLT), consisting of grade 3 fatigue, weakness, and mucositis. Therefore, the MTD was not reached in the 3 planned dose levels of the sequential schedule. One DLT (grade 3 fatigue) occurred in 6 patients treated at dose level 2 of the concurrent schedule. Most common drug-related non-hematological toxicities of any grade (all CTCAE grades 1 or 2) were nausea (71%), fatigue (54%), diarrhea (54%), vomiting (42%), anorexia (25%), constipation (13%), abdominal pain (13%), dehydration (13%), and headache (13%). No other non-hematological grade 3 or 4 toxicities were observed. Of the 25 evaluable patients, one patient achieved an incomplete CR (without neutrophil recovery), one a morphologic leukemia-free state (without blood count recovery), and three partial remissions (1 achieved red cell transfusion independency and a second normalization of platelet counts). Seven of these patients remain on study for 2.7 to 13.5+ months. Correlative studies examining histone acetylation and gene promoter methylation in leukemic cells at baseline and after treatment, as well as plasma pharmacokinetic levels for both decitabine and vorinostat are being evaluated. Conclusions: The combination of decitabine and vorinostat is safe, well-tolerated, and has clinical activity in patients with AML. Enrollment is ongoing.

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Final Results of a Phase I Study of the Fc Engineered CD19 Antibody XmAb®5574 (MOR00208) in Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL).

Blood ◽

10.1182/blood.v120.21.2894.2894 ◽

2012 ◽

Vol 120 (21) ◽

pp. 2894-2894 ◽

Cited By ~ 1

Author(s):

Jennifer A. Woyach ◽

Farrukh Awan ◽

Ian W. Flinn ◽

Rolondo Enoch ◽

Paul A. Foster ◽

...

Keyword(s):

High Risk ◽

Febrile Neutropenia ◽

Adverse Events ◽

Phase I ◽

B Cell ◽

Dose Level ◽

Phase I Trial ◽

Hematologic Toxicity ◽

B Cell Malignancies ◽

Dose Levels

Abstract Abstract 2894 Antibody (Ab) therapies such as the CD20 monoclonal abs rituximab and ofatumumab are commonly used in CLL alone and in combination with chemotherapy, however, CD20 density is low on CLL cells, suggesting this may not be the ideal target. CD19, which is ubiquitously expressed on CLL cells and those of other B cell malignancies is a reasonable candidate for ab targeting. XmAb5574 is a novel humanized IgG1 CD19 monoclonal ab with an engineered Fc region to enhance Fc gamma receptor binding affinity. In vitro, this ab demonstrates direct cytotoxicity and antibody dependent cellular phagocytosis similar to rituximab, however, shows enhanced natural killer antibody dependent cellular cytotoxicity compared to other therapeutic abs used in CLL (Awan, FT Blood 2009). We have performed a first in human trial of this ab as a single agent in relapsed or refractory (R/R) CLL, and present the results in this report. This study is a multi-institutional phase I trial of XmAb5574 in patients (pts) with R/R CLL. Eligible pts were those with CLL who had at least 1 prior therapy and required treatment by International Working Group on CLL (IWCLL) 2008 Guidelines (Hallek, M Blood 2008), had Eastern Cooperative Oncology Group Performance Status <3, had platelets ≥50,000/mm3, and had adequate organ function. Primary endpoints were to determine maximal tolerated dose (MTD), describe toxicity, and characterize pharmacokinetics (PK). A secondary endpoint was to explore efficacy. An accelerated titration design was used in which 1 pt was accrued to the first two dose levels provided there were no dose limiting toxicities (DLT) or ≥ grade 2 adverse events (AE), and then a standard 3×3 design was employed from dose level 3 forward. Dose levels included 0.3, 1, 3, 6, 9, and 12 mg/kg with an expansion to a total of 16 pts at the MTD. XmAb5574 was administered as an intravenous infusion on days 1, 4, 8, 15, and 22 of cycle (C) 1, and on days 1, 8, 15, and 22 of C2. Toxicity was assessed using the National Cancer Institute's Common Criteria for Adverse Events v4.0 for non-hematologic toxicity, and IWCLL 2008 guidelines for hematologic toxicity. Disease response assessment by physical exam was performed on C1D28, C2D28, and 4, 8, and 12 weeks after the end of C2. Radiographic assessment was performed C2D28. 27 pts were enrolled to this phase I trial. The median age of all pts was 66 years (range 40–84). The pts were generally high risk: 14 (52%) had high-risk disease by Rai stage, 8 (30%) had del(11q22.3) and 10 (37%) had del(17p13.1) by FISH, and 24 (89%) had IgVH unmutated disease. The median number of prior therapies was 4 (range 1–14). Toxicity with this agent was modest. Dose escalation continued without dose limiting toxicity (DLT) until the highest dose level, in which one patient experienced grade 4 neutropenia associated with febrile neutropenia which required dose discontinuation. 100% of patients experienced any AE, with the majority of AE being grade 1–2. The most common AEs were infusion reactions in 18 patients (67%), all of which were grade 1 or 2. Treatment-related Grade 3 or 4 AEs occurred in 5 pts (19%), and included neutropenia (n=3), thrombocytopenia (n=2), increased aspartate aminotransferase (AST) (n=1), febrile neutropenia (n=1), and tumor lysis syndrome (n=1). All were on the 12 mg/kg dose level except one pt receiving 1mg/kg who experienced neutropenia. Overall response rate by IWCLL 2008 criteria is 11%, all of which have been partial responses (PR). Using IWCLL 1996 response criteria which does not include CT scan assessment of disease resulted in a PR in 13 pts (42%). Only 2 pts had PD at the 8 week evaluation point. Responses occurred at the 6, 9, and 12 mg/kg dose levels. All objective responses were in pts categorized as CLL as opposed to SLL, and no patients with lymph nodes >5cm responded. PK was best modeled by a two-compartment model. Half-life was 14 days, with clearance 5mL/day/kg that was not dose-dependent. Across the dose range, area under the curve increased in a dose-proportional manner, while maximum concentration increased in a less than proportional manner. A steady-state was reached at or before infusion 9. XmAb5574 shows acceptable toxicity and signs of preliminary efficacy in patients with high-risk, heavily pretreated CLL. These results justify movement into phase II study in CLL as well as other B cell malignancies. Modest toxicity, in particular infectious toxicity, will potentially allow combinations with other active agents in CLL. Disclosures: Enoch: Xencor, Inc.: Employment. Foster:Xencor, Inc: Consultancy.

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A humanized antibody against CD40 (SGN-40) is well tolerated and active in non-Hodgkin’s lymphoma (NHL): Results of a phase I study

Journal of Clinical Oncology ◽

10.1200/jco.2006.24.18_suppl.7534 ◽

2006 ◽

Vol 24 (18_suppl) ◽

pp. 7534-7534 ◽

Cited By ~ 11

Author(s):

A. Forero-Torres ◽

R. R. Furman ◽

J. D. Rosenblatt ◽

A. Younes ◽

K. Harrop ◽

...

Keyword(s):

Phase I ◽

B Cell ◽

Dose Escalation ◽

Phase I Study ◽

Cell Function ◽

Maximum Tolerated Dose ◽

Pharmacokinetic Data ◽

Cell Transplant ◽

Humanized Antibody ◽

Phase Ii Studies

7534 Background: CD40 is a member of the TNF receptor family and is widely expressed on hematologic malignancies of B-cell origin. SGN-40 is a humanized antibody against CD40 with effector cell function and mild agonistic activity. Preclinical toxicity studies and efficacy data supported initiation of a multi-institutional phase I study to test the safety, pharmacokinetics, immunogenicity, and efficacy of SGN-40 in patients with relapsed NHL. Methods: Cohorts of 3–6 pts were treated weekly with a maximum dose of 2, 3, or 4 mg/kg/wk SGN-40. A dose escalation schedule is used such that patients receive 1 mg/kg on D1 and D4, 2 mg/kg on D8, and higher doses on weeks 3–5. Responding patients may receive a second cycle. Further dose escalation up to 8 mg/kg is planned. Results: 16 pts have been treated with multiple histologic subtypes: follicular (1), marginal zone (MZL; 1), mantle cell (4), and diffuse large B-cell (DLBCL; 10). One patient (2 mg/kg) developed a reversible Grade 3 unilateral conjunctivitis and ipsilateral loss of visual acuity. No other dose limiting toxicity has been observed up to 4 mg/kg. Preliminary pharmacokinetic data suggest that the antibody has a relatively short half-life, perhaps reflecting a route of elimination or binding that is not saturated at current doses. Two partial responses have been observed at 3 mg/kg (1 MZL, 1 DLBCL) and one partial response has been observed at 4 mg/kg dose (DLBCL relapsed after autologous stem cell transplant with small volume tumor). Conclusions: Using an intra-patient dose escalation schedule, SGN-40 has been well-tolerated at doses up to 4 mg/kg/wk. Further dose-escalation is ongoing to determine the maximum tolerated dose. Three objective responses have been seen, including two in patients with extensively treated aggressive disease. Correlative studies are underway measuring soluble CD40, cytokine release, effect of FcR polymorphisms, and SGN-40-induced immunogenicity. Given the favorable tolerability and activity, phase II studies in NHL are planned. [Table: see text]

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Phase I study of ATN-224 in patients (pts) with advanced solid tumours

Journal of Clinical Oncology ◽

10.1200/jco.2006.24.18_suppl.2065 ◽

2006 ◽

Vol 24 (18_suppl) ◽

pp. 2065-2065

Author(s):

S. A. Lowndes ◽

A. Adams ◽

A. Timms ◽

M. Middleton ◽

C. Hayward ◽

...

Keyword(s):

Phase I ◽

Dose Level ◽

Phase I Study ◽

Surrogate Marker ◽

Maximum Tolerated Dose ◽

Target Range ◽

Concurrent Administration ◽

Rapid Reduction ◽

Copper Chelation ◽

Copper Depletion

2065 Background: Copper chelation reduces the secretion of many angiogenic factors and reduces tumour growth and microvascular density in animal models. ATN-224 is a second generation analogue of ammonium tetrathiomolybdate, which reportedly can stabilise disease but was limited by the slow onset of copper depletion (50–60 days). Preclinical studies suggest ATN-224 may act primarily by superoxide dismutase 1 (SOD-1) inhibition. The aim of our phase I study was to reduce serum copper levels, as measured by ceruloplasmin (Cp), to 5–15 mg/dl (normal 16–60) in 14–21 days, to determine the pharmacokinetic profile, and to evaluate dose-limiting toxicities. Methods: Cohorts of pts were treated with escalating doses of ATN-224, twice daily, until copper depletion, followed by a titrated maintenance dose. Serum Cp was used as a surrogate marker of copper levels and was titrated to a target range of 5–15mg/dL (normal 16–60). Results: 18 pts have received 54 cycles of ATN-224. Tumours were breast (4), renal (2), melanoma (2), colon (2), and a variety of other types (1 each). Pts received ATN 224 loading doses in cohorts of 1 to 6 pts: 150 (1), 210 (2), 240 (1), 270 (6), 300 (5), and 330 mg/day (3). Mean age was 56 yrs (range 37–78) and PS 0–2. Mean baseline Cp was 39.6 (range 22–63 mg/dL). The maximum administered dose was 330 mg/day where grade 3 lethargy was observed in 3 pts. Of the 4 pts at the maximum tolerated dose of 300 mg/day who have currently completed the loading schedule, all 4 have achieved a reduction of Cp to within 10% of the target range within 21 days. Other toxicities at this dose level included sulphur burps (Gr 1), vomiting (Gr 2), neutropenia (Gr 2), and anaemia (Gr 3). Toxicities reduced in the second and subsequent cycles when doses were titrated downward to maintain Cp levels in target range. PK data indicate greater absorption of ATN 224 and more rapid reduction in Cp with concurrent administration of a proton pump inhibitor. Stable disease of >6 months was observed in 4 pts. Conclusions: Oral ATN-224 is a well-tolerated therapy and at a loading dose of 300 mg/day leads to a reduction of serum Cp levels to 20% normal within 21 days. This will be the recommended starting dose level for phase II study. (Sponsored by Cancer Research UK; funded by Attenuon, LLC). [Table: see text]

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