Phase I trial of ZD1694, a new folate-based thymidylate synthase inhibitor, in patients with solid tumors.

PURPOSE To perform a phase I clinical and pharmacologic study of ZD1694 (Tomudex, Alderley Park, United Kingdom), a new folate-based thymidylate synthase (TS) inhibitor, in patients with advanced malignancy. PATIENTS AND METHODS From February 1991 to January 1993, 61 patients with a range of solid tumor received 161 courses of ZD1694 given as a single 15-minute intravenous infusion every 3 weeks, at escalating doses from 0.1 to 3.5 mg/m2. Pharmacokinetic (PK) analysis was performed with the first two courses of treatment. There were 33 men and 28 women with a median age of 53 years (range, 21 to 73). Fifty-five patients (90%) had previously received chemotherapy. RESULTS Reversible liver toxicity and dose-related gastrointestinal (GI) and bone marrow toxicity occurred at > or = 1.6 mg/m2. Liver function usually returned to normal with repeated treatment, but GI and bone marrow toxicities generally became more severe. No renal toxicity was observed. The maximum-tolerated dose (MTD) was 3.5 mg/m2, at which, in addition to antiproliferative toxicities, four of six patients (67%) developed severe malaise that consisted of anorexia, nausea, and asthenia, with rapidly decreasing performance status that limited re-treatment. Abnormal liver function was also seen in four patients (67%). At 3.0 mg/m2, grades III and IV diarrhea were seen in six of 23 patients (26%) and grade IV myelosuppression in two others. Liver toxicity was self-limiting and not associated with severe malaise. Two patients had a partial response to treatment. PK analysis showed that plasma elimination was triexponential, with pronounced variability in the mean terminal half-life (t1/2gamma) for a given dose ranging from 8.2 to 105 hours. There was a linear relationship between dose and both the area under the concentration-time curve (AUC) and maximum concentration (Cmax), but no clear association between these parameters and response or toxicity. CONCLUSION The dose of ZD1694 recommended for phase II trials is 3.0 mg/m2.

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Phase I study of repeated cycles of high-dose cyclophosphamide, etoposide, and cisplatin administered without bone marrow transplantation.

Journal of Clinical Oncology ◽

10.1200/jco.1990.8.10.1728 ◽

1990 ◽

Vol 8 (10) ◽

pp. 1728-1738 ◽

Cited By ~ 33

Author(s):

J A Neidhart ◽

W Kohler ◽

C Stidley ◽

A Mangalik ◽

A Plauche ◽

...

Keyword(s):

Bone Marrow ◽

Phase I ◽

Performance Status ◽

Complete Response ◽

High Dose ◽

Hematologic Toxicity ◽

Tumor Type ◽

Advanced Malignancy ◽

Prior Therapy ◽

And Performance

Forty-two patients with advanced malignancy judged unlikely to respond to standard treatment received high-dose combination chemotherapy with cyclophosphamide, etoposide, and cisplatin in a phase I trial. Twenty-two of these patients who had at least a partial response (PR) to the first cycle of therapy received a second cycle, and eight patients received three or more cycles of therapy. Bone marrow replacement was not used. The maximum-tolerated doses (MTDs) were cyclophosphamide 2.5 g/m2 on days 1 and 2; etoposide 500 mg/m2 on days 1, 2, and 3; and cisplatin 50 mg/m2 on days 1, 2, and 3. Hematologic toxicity was not dose-limiting by study design. Recovery to an absolute granulocyte count above 100/microL occurred at a median of 9 days from onset (range, 3 to 23 days) at the MTD. Recovery was delayed after the third cycle. Only one patient on his third cycle failed to recover peripheral blood counts and died of sepsis an day 43. Hematologic toxicity was not dose-dependent. Nonhematologic toxicities included emesis, fatigue, alopecia, diarrhea, and anorexia and were generally well tolerated. The dose-limiting toxicities were fatal pulmonary or cardiac toxicities in five of nine patients treated at the highest dose level. Patients likely to do well can be selected by tumor type, response to prior therapy, and performance status. Nine of 36 assessable patients had a complete response (CR) and 13 a PR for a response rate of 61%. Five patients (12%) remain alive and free of disease at 15 to 32 months. Repeated cycles of dose-intensive combination therapy can produce long-term disease-free remissions in patients with refractory tumor types. The toxicity of the regimen is acceptable if patients are carefully selected.

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Evaluation of ON01910.Na In Patients with a Myelodysplastic Syndrome (MDS) or Acute Myeloid Leukemia (AML) Relapsed or Refractory to Hypomethylating Agents: A Phase I Study

Blood ◽

10.1182/blood.v116.21.2944.2944 ◽

2010 ◽

Vol 116 (21) ◽

pp. 2944-2944

Author(s):

Lewis R Silverman ◽

Shyamala C. Navada ◽

Rosalie Odchimar-Reissig ◽

Vesna Najfeld ◽

Takao Ohnuma ◽

...

Keyword(s):

Bone Marrow ◽

Phase I ◽

Peripheral Blood ◽

Study Cohort ◽

Pharmacokinetic Studies ◽

Induction Phase ◽

Bone Marrow Toxicity ◽

Monosomy 7 ◽

Biologic Activity ◽

Hypomethylating Agent

Abstract Abstract 2944 Background: ON 01910.Na a novel benzyl styryl sulfone derivative is under clinical development in hematologic malignancies. It is a multi-kinase/PI3 kinase inhibitor that promotes G2/M arrest and selectively induces apoptosis in cancer cells. Leukemic cells exhibit significantly higher levels of sensitivity to ON 01910.Na compared to normal marrow progenitors and increasing cytotoxicity upon prolonged and repetitive exposure (Skidan Proc AACR 2006; Chen Proc AACR 2008). Azacitidine (AzaC), is first line therapy for patients (pts) with higher-risk MDS and produces a response rate of 50%. Pts relapsed or refractory to hypomethylating based therapies have a poor prognosis and there are no accepted effective second line treatments, thus a need for new agents. Methods: A phase I/II study of ON 01910.Na is being conducted in pts with hematological malignancies. In the phase I component pts are entered in cohorts of escalating doses in a classic 3+3 design in doses ranging from 650 up to 1700 mg/m2/d continuous IV infusion (CIV) for durations from 72 hours up to 144 hours every 2 weeks (1 cycle) for 4 cycles of treatment during the induction phase. Subsequent treatments are administered every 3 to 4 weeks. A CBC is performed weekly and a bone marrow (BM) is performed at baseline and week 4, 8, and then q3 months thereafter. Pts with higher-risk disease had to have failed a hypomethylating agent. Results: Ten pts with MDS or AML relapsed/refractory to a hypomethylating agent have been treated with ON 01910.Na thus far (table 1). The study cohort comprised pts with a diagnosis (Dx) RAEB-2 (4 pts), RAEB-T (1 pt), and AML (5 pts) (median age of 75 years). Their cytogenetic profile included 1 pt with normal, 2 with intermediate (+8), and 7 pts with poor risk cytogenetics (monosomy 7 and/or complex). Patients were treated between 5 and 70 weeks. Responses according to IWG 2006 criteria were observed in the BM and peripheral blood: Marrow CR (3), hematologic improvement (HI-P) (2); erythroid (1) platelet (1). An additional 2 pts had a >50% BM blast decrease from baseline but not to <5%. Thus, 5/10 (50%) demonstrate a bone marrow response. Survival of these pts was 7.3, 15.7, and 16.4 months; one patient remains on study 5+ months. Four of the five responders had MDS at the initiation of treatment: RAEB-2 (3), CMMoL (1), AML (1). Responders had monosomy 7 (2), trisomy 8 (1) and complex cytogenetics (2). One pt had an elimination of the MDS clone and the others had persistence of the abnormal karyotype throughout their treatment course. Five pts had SD without HI at 4 weeks, 2 pts progressed to AML. All 5 non-responders had AML; 4 with a proliferative course. These latter received only 2 (2) or 3 (3) cycles before succumbing to disease related infectious complications. Survival for these patients ranged from 1.3 – 2 months with a median duration on study of 42 days. The most frequent side effects grade2 2 for all pts included fatigue, anorexia, nausea, and dysuria in patients receiving extended duration infusions. One pt had a grade 3 urinary frequency. No hematologic toxicities occurred and no bone marrow toxicity or hypoplasia was noted. Pharmacokinetic studies are ongoing, data to date demonstrate no evidence of drug accumulation in patients who are treated repeatedly. Conclusion: ON 01910.Na appears to be safe and well tolerated in patients with refractory or relapsed MDS and AML. ON 01910.Na has biologic activity with reduction in BM blasts, eradication of the MDS clone and improvement in the peripheral blood counts in some pts. These effects are associated with increased survival albeit in limited numbers of pts treated thus far. Further study of ON 01910.Na is warranted to better define biologic activity, appropriate target populations and to define mechanism of action. Disclosures: Silverman: Onconova Therapeutics Inc: Research Funding, Research support of Clinical Trial. Wilhelm:Onconova Therapeutics Inc: Employment, Equity Ownership.

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Phase I trial of esorubicin (4'deoxydoxorubicin).

Journal of Clinical Oncology ◽

10.1200/jco.1984.2.9.1034 ◽

1984 ◽

Vol 2 (9) ◽

pp. 1034-1039 ◽

Cited By ~ 8

Author(s):

H S Garewal ◽

A Robertone ◽

S E Salmon ◽

S E Jones ◽

D S Alberts ◽

...

Keyword(s):

Bone Marrow ◽

Phase I ◽

Phase I Study ◽

Primary Objective ◽

Response Analysis ◽

Phase Ii Trials ◽

Premature Ventricular Contractions ◽

Skin Reactions ◽

Local Skin ◽

Starting Dose

A phase I study of 4'deoxydoxorubicin (esorubicin) was performed on an every-21-day bolus intravenous (IV) schedule in 36 patients with advanced cancer. Thirty-four patients were evaluable for toxicity analysis. Toxicity included mild nausea, occasional local skin reactions, and mild to moderate alopecia. Myelo-suppression was dose limiting. Clinically evident congestive heart failure was not observed. However, two patients developed premature ventricular contractions. Overall, esorubicin was better tolerated than doxorubicin at equally potent doses. Although response analysis was not the primary objective of this phase I study, minor responses were observed in melanoma, breast cancer, lymphoma, and gastric cancer. On the basis of this study, a starting dose of 30 mg/m2 IV every 21 days is recommended for good-risk patients with escalation to 32.5 mg/m2 depending on bone marrow tolerance. For patients with poor bone marrow reserve, a starting dose of 25 mg/m2 every 21 days is recommended. Phase II trials with esorubicin in this dosage schedule are clearly warranted in a wide variety of metastatic neoplasms including a substantial population of patients who have not received prior chemotherapy.

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Plerixafor, G-CSF and Azacitidine For The Treatment Of MDS: Results Of a Phase I Trial

Blood ◽

10.1182/blood.v122.21.2816.2816 ◽

2013 ◽

Vol 122 (21) ◽

pp. 2816-2816

Author(s):

Mark A. Schroeder ◽

Marcus Grillot ◽

Teresa Reineck ◽

Meagan A Jacoby ◽

Rizwan Romee ◽

...

Keyword(s):

Cell Cycle ◽

Bone Marrow ◽

Phase I ◽

Research Funding ◽

Phase I Trial ◽

Response Rates ◽

Response To Treatment ◽

Hematologic Toxicity ◽

Oncology Research ◽

Grade 3

Abstract Azacitidine has been shown to prolong survival and delay progression to leukemia in intermediate-2 and high risk myelodysplastic syndrome (MDS) in a randomized study compared to best supportive care. The combination of G-CSF and plerixafor is synergistic in increasing the release of stem and progenitor cells from the bone marrow through disruption of critical bone marrow stromal interactions including the CXCR4 / CXCL12 axis. The interaction of bone marrow stromal cells with the MDS tumor clone may play a roll in pathogenesis and response to treatment. We hypothesized that resistance of MDS to azacitidine may be related to MDS tumor and BM-stromal cell interactions, and disruption of these interactions by treatment with plerixafor + G-CSF could enhance sensitivity to azacitidine, thus improving complete and partial response rates. We conducted a phase I trial to investigate the safety and tolerability of plerixafor + G-CSF in combination with azacitidine in adult (18 years or older) MDS patients. Secondary objectives included response rates and biologic correlates evaluating: kinetics, phenotype, cell cycle status and kinetics of mobilization of MDS blasts compared to normal stem cells in select patients with informative cytogenetics. Major inclusion criteria included MDS defined by WHO criteria, 5 – 20% blasts on bone marrow aspirate, and at least one cytopenia in one cell lineage. Subjects receiving prior hypomethylating therapy were allowed. A standard 3+3 trial with 3 cohorts (320, 440, and 560 mcg/kg/day SC) was conducted. Dose limiting toxicity was defined as grade 3 or higher non-hematologic toxicity and hematologic toxicity of leukostasis or tumor lysis. Myelosuppression, infection, grade III nausea, fatigue, weight loss and electrolyte abnormalities were not considered dose limiting. Subjects initially received G-CSF 10 mcg/kg subcutaneous (SC) daily D1 – D8, plerixafor SC daily D3 – D8 and azacitidine 75mg/m2 SC D3 – D8, 4 hours after plerixafor administration. The trial was amended after the first 3 subjects to reduce G-CSF dose and administration to 5 days. Results Two of the first three subjects enrolled in cohort 1 (320 mcg/kg/d plerixafor) had leukocytosis. The trial was amended to reduce the G-CSF dose (10 mcg/kg to 5 mcg/kg) and duration (8 days to 5 days) because of this. One subject had symptoms of leukostasis with a WBC reaching nearly 100K/uL and a subsequent subject developed hyperleukocytosis (WBC = 80K/uL) without leukostasis. The trial was amended to reduce the G-CSF to 5 days concurrent with plerixafor and azacitidine along with defining dose holding parameters for G-CSF and plerixafor if the peripheral blood WBC exceeded 40K/uL or if absolute blast count exceeded 10K/uL. Since amendment of the trial, 64 subjects have been screened and 20 subjects have been enrolled and are evaluable. Subjects included 65% males, median age 67, and MDS diagnosis at study entry including 6/18 (33%) RAEB-1 and 12/18 (67%) RAEB-2. 5/18 subjects (28%) had plerixafor and G-CSF held during treatment because of leukocytosis. 9/18 subjects (50%) had received no prior treatment for their MDS. DLTs were experienced in Cohort 1 related to thrombocytosis (n =1) and in Cohort 2 related to atrial fibrillation (n = 1) with near syncope. Major non-hematologic grade 3 or 4 adverse events included epistaxis, hypocalcemia, GI bleed, headache, dyspnea, infection with neutropenia, and bone pain. The MTD was determined to be 560mcg/kg plerixafor SC with no subjects (n = 6) in this cohort experiencing a DLT. The median number of cycles completed was 3. Reasons for stopping treatment included progression to leukemia (n = 6), physician choice (n = 2), withdrawal of consent (n = 1), adverse event (n = 2). Best response in those evaluable after completing 2 cycles of treatment (n = 14) showed marrow CR in 5/14 (36%, 3 in those not previously treated for MDS), stable disease in 5/14 (36%) and progressive disease 4/14 (29%). Conclusion Plerixafor plus G-CSF in combination with azacitidine was well tolerated in the studied MDS patients when given over 5 days and may be associated with encouraging response rates. Correlative studies are ongoing to evaluate changes in cell cycle, apoptosis and preferential mobilization of blasts using this regimen. We are currently enrolling an expanded cohort of 7 subjects at the MTD dose to evaluate preferential mobilization of blasts with plerixafor alone in cases using informative cytogenetics. Disclosures: Schroeder: Celgene: Research Funding; Sanofi Oncology: Research Funding. Off Label Use: Plerixafor and G-CSF for the treatment of MDS. Welch:Eisai: Research Funding. Stockerl-Goldstein:Millennium: Speakers Bureau; Celgene : Speakers Bureau.

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Intraperitoneal aerosolized nanoparticle albumin based paclitaxel (NAB-PTX) for irresectable peritoneal metastases: A first in human phase I study.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.4065 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 4065-4065

Author(s):

Wim Ceelen ◽

Louis Sandra ◽

Leen Van de Sande ◽

Martin Graversen ◽

An Vermeulen ◽

...

Keyword(s):

Ovarian Cancer ◽

Overall Survival ◽

Phase I ◽

Liver Toxicity ◽

Surgical Site Infections ◽

Peritoneal Metastases ◽

Phase Ii Trials ◽

Surgical Morbidity ◽

Visual Analogue Pain ◽

Grade 3

4065 Background: Pressurized intraperitoneal aerosolized chemotherapy (PIPAC) was recently introduced in the palliative treatment of peritoneal metastases (PM). Results from preclinical experiments suggest that intraperitoneal (IP) Nab-PTX may result in superior efficacy compared to solvent based paclitaxel (PTX). We performed a phase I first-in-human trial of PIPAC using Nab-PTX in patients with PM from upper gastrointestinal, breast, or ovarian cancer. Methods: Eligible patients with biopsy-proven PM underwent up to three PIPAC treatments using Nab-PTX with a four-week interval at two university hospitals. Patients underwent laparoscopy with IP nebulization of Nab-PTX over 5 min; the procedure was completed after 30 min. The dose of Nab-PTX was escalated from 35 to 140 mg/m2 using a Bayesian approach until the maximally tolerated dose (MTD) was reached. Secondary endpoints included surgical morbidity, pharmacokinetics (PK), histological treatment response, and overall survival. Blood and tissue samples were taken after each PIPAC procedure. Population PK analysis was performed using Monolix version 2020R1. Quality of life was measured using the EORTC QLQ-C30 questionnaire and visual analogue pain scales (VAS). Results: Twenty-three patients were included. The primary tumor was gastric cancer (55%), ovarian cancer (20%), hepatobiliary or pancreatic cancer (15%), breast cancer (5%), and miscellaneous (5%). No dose limiting toxicity was observed. Grade 3 thrombopenia was observed in one patient allocated to a dose of 90 mg/m2. One patient allocated to the highest dose experienced grade 3 neutropenia one week after each PIPAC. The most frequent treatment-related toxicities were liver toxicity (grade 1 to 3, 75%) and anemia (grade 1 to 3, 70%). Eight patients (40%) showed surgical site infections including wound infection and wound dehiscence (grade 1 to 3), four of whom required treatment with antibiotics. Treatment was associated with histological response in 35% of patients, while stable disease and progressive disease were found in 35% and 30%, respectively. The absorption of PTX continued long after the end of the procedure (30 min), with the Tmax reached between 2 and 6 h after initiation of the procedure. Median tumor PTX concentrations suggested accumulation: 9.37 ng/mg, 14.78 ng/mg and 25.75 ng/mg after the first, second and third PIPAC, respectively. EORTC global health, functional, and symptom scores as well as VAS scores remained stable throughout the treatment period. Overall survival after one year was 57%. Conclusions: PIPAC with Nab-PTX may be applied safely up to a dose of 140 mg/m2 and results in a favorable PK profile and promising anticancer activity. At the MTD of 140 mg/m2, considerable surgical site infections and liver toxicity were observed. Therefore, the recommended dose for future phase II trials is 112.5 mg/m2. Clinical trial information: NCT03304210.

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A phase I study of MGMT-P140K transfected hematopoetic progenitor cells (HPC) combined with TMZ/O6BG dose escalation for newly diagnosed, MGMT unmethylated glioblastoma: Tolerance and evidence of survival benefit.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.2062 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. 2062-2062

Author(s):

Andrew E. Sloan ◽

Lisa Roger ◽

Chris Murphy ◽

Jane Reese ◽

Hillard M. Lazarus ◽

...

Keyword(s):

Bone Marrow ◽

Phase I ◽

Dose Escalation ◽

Dna Methyltransferase ◽

Tumor Response ◽

Insertion Site ◽

Hematologic Toxicity ◽

Bone Marrow Toxicity ◽

Newly Diagnosed ◽

Mgmt Gene

2062 Background: GBM is the most common malignant brain tumor with a median survival of 15 months despite surgery and radio-chemotherapy. The most important mechanism of TMZ resistance is the O6-methylguanine-DNA methyltransferase (MGMT) gene which repairs temozolamide-induced DNA methylation. The MGMT inhibitor O6-benzylguanine (BG) demonstrated efficacy in depleting MGMT and maximizing tumor response in early phase clinical trials. However, MGMT expression is also low in hematopoietic cells, so this approach led to unacceptable bone marrow toxicity and thus has been abandoned. We hypothesized that chemoprotection of hematopoietic HPC with an MGMT mutant (MGMT-P140K) characterized by normal methyltransferase activity, coupled with low affinity for BG would maximize anti-tumor response while enabling patients to tolerate TMZ & BG dose escalation with minimal toxicity. A phase I trial was performed to test this hypothesis. Methods: 10 adults with newly diagnosed MGMT unmethylated, IDH-1 WT, GBM underwent standard surgery and radiation, followed by transplantation with autologous CD34+ HPC engineered to express MGMT-P140K using a lentiviral vector. We tested tolerance and efficacy of three different paradigms for conditioning bone marrow and re-infusion of HPC. To assess chemo-protection, patients’ blood counts and transgene marking were monitored during and after treatment, as was toxicity, response, and progression-free and overall survival. Results: Treatment was moderately toxic with 3/10 patients suffering grade 3-4 hematologic toxicity; no high grade non-hematologic toxicity was observed . Viral transduction rates ranged from 3-75% and were clearly improved in Arm III utilizing BCNU conditioning and intra-patient dose escalation of TMZ/O6GB. In patients tolerating 3 cycles or more, P140K-MGMT gene markings in peripheral blood and bone marrow cells increased 3-26-fold with only mild (Grade 2-3) mylosuppression consistent with chemo-protection as hypothesized. Median PFS and OS was 22 and 31 months respectfully, and three patients in Arm III are healthy and progression free at 36-39 months. OS exceeded RPA predicted survival by 3.3-fold suggesting clinical benefit. Viral insertion site analysis demonstrate lack of clonal dominance. Conclusions: P140K-MGMT transfected HPC enables TMZ/ BG dose escalation with acceptable toxicity and increased survival in a small cohort of selected patients. A phase II study is ongoing. Clinical trial information: NCT01269424.

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CTNI-49. PHASE I STUDY OF MGMT-P140K TRANSFECTED HEMATOPOETIC PROGENITOR CELLS COMBINED WITH TMZ/O6BG DOSE ESCALATION FOR NEWLY DIAGNOSED, UNMETHYLATED GLIOBLASTOMA: TOLERANCE AND EVIDENCE OF SURVIVAL BENEFIT

Neuro-Oncology ◽

10.1093/neuonc/noaa215.215 ◽

2020 ◽

Vol 22 (Supplement_2) ◽

pp. ii53-ii53

Author(s):

Andrew E Sloan ◽

Hua Fung ◽

Jane Reese ◽

Lisa Rgers ◽

Christopher Murphy ◽

...

Keyword(s):

Bone Marrow ◽

Phase I ◽

Dose Escalation ◽

Dna Methyltransferase ◽

Lentiviral Vector ◽

Insertion Site ◽

Hematologic Toxicity ◽

Bone Marrow Toxicity ◽

Newly Diagnosed ◽

Mgmt Gene

Abstract INTRODUCTION GBM has median survival of 12 months despite current SOC therapy. The most important mechanism of TMZ resistance is the O6-methylguanine-DNA methyltransferase (MGMT) gene. The MGMT inhibitor O6-benzylguanine (BG) demonstrated efficacy in depleting MGMT but approach led to unacceptable bone marrow toxicity and has thus been abandoned. We hypothesized that chemoprotection of hematopoietic HPC with an MGMT mutant (MGMT-P140K) characterized by normal methyltransferase activity, coupled with low affinity for BG would maximize anti-tumor response while enabling patients to tolerate TMZ & BG dose escalation with minimal toxicity. A phase I trial was performed to test this hypothesis. METHODS 10 adults with newly diagnosed MGMT unmethylated, IDH-1 WT, GBM underwent standard surgery and radiation, followed by transplantation with autologous CD34+ HPC transfected with MGMT-P140K using a lentiviral vector. We tested tolerance and efficacy of three different paradigms for conditioning bone marrow and re-infusion of HPC. RESULTS Treatment was moderately toxic with 3/10 patients suffering grade 3–4 hematologic toxicity; no high grade non-hematologic toxicity was observed. Viral transduction rates ranged from 3–75% and were clearly improved in Arm III utilizing BCNU conditioning and intra-patient dose escalation of TMZ/O6GB. In patients tolerating 3 cycles or more, P140K-MGMT gene markings in peripheral blood and bone marrow cells increased 3-26-fold with only mild (Grade 2–3) myelosuppression consistent with chemo-protection as hypothesized. Median PFS and OS was 24 and 33 months respectfully, and three patients in Arm III were progression free at 36 months with one progression free at 48 months. OS exceeded RPA & Nomogram predicted survival by 3.6-fold, suggesting clinical benefit. Viral insertion site analysis demonstrate no clonal dominance. CONCLUSIONS P140K-MGMT transfected HPC enables TMZ/ BG dose escalation with acceptable toxicity and increased survival in a small cohort of selected patients. A U-01 funded phase II study is ongoing at UH and NIH.

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Phase I/II study of iodine 125-labeled monoclonal antibody A33 in patients with advanced colon cancer.

Journal of Clinical Oncology ◽

10.1200/jco.1996.14.6.1787 ◽

1996 ◽

Vol 14 (6) ◽

pp. 1787-1797 ◽

Cited By ~ 109

Author(s):

S Welt ◽

A M Scott ◽

C R Divgi ◽

N E Kemeny ◽

R D Finn ◽

...

Keyword(s):

Monoclonal Antibody ◽

Bone Marrow ◽

Colon Cancer ◽

Phase I ◽

Gastrointestinal Symptoms ◽

Additional Patient ◽

Bone Marrow Toxicity ◽

Mixed Response ◽

Iodine 125

PURPOSE A phase I/II study was designed to determine the maximum-tolerated dose (MTD) of iodine 125-labeled monoclonal antibody A33 (125I-mAb A33), its limiting organ toxicity, and the uptake and retention of radioactivity in tumor lesions. PATIENTS AND METHODS Patients (N = 21) with advanced chemotherapy-resistant colon cancer who had not received prior radiotherapy were treated with a single 125I-mAb A33 dose. 125I doses were escalated from 50 to 350 mCi/m2 in 50-mCi/m2 increments. Radioimmunoscintigrams were performed for up to 6 weeks after 125I-mAb A33 administration. RESULTS All 20 patients with radiologic evidence of disease showed localization of 125I to sites of disease. Twelve of 14 patients, who underwent imaging studies 4 to 6 weeks after antibody administration, had sufficient isotope retention in tumor lesions to make external imaging possible. No major toxicity was observed, except in one patient with prior exposure to mitomycin who developed transient grade 3 thrombocytopenia. Although the isotope showed variable uptake in the normal bowel, gastrointestinal symptoms were mild or absent, and in no case did stools become guaiac-positive. The MTD was not reached at 125I doses up to 350 mCi/m2. However, cytotoxicity assays demonstrated that patients treated with the highest dose had sufficiently high serum levels of 125I-mAb A33 to lyse colon cancer cells in vitro. Among 21 patients, carcinoembryonic antigen (CEA) levels returned to normal in one patient and decreased by 35% and 23%, respectively, in two patients; one additional patient had a mixed response on computed tomography. Additional, significant responses were observed in those patients treated with chemotherapy [carmustine [BCNU], vincristine, flourouracil, and streptozocin [BOF-Strep]) after completion of the 125I-mAb A33 study. CONCLUSION Low-energy emission radioimmunotherapy with doses of up to 350 mCi/m2 of 125I-mAb A33 did not cause bowel or bone marrow toxicity. The modest antitumor activity in these heavily pretreated patients is encouraging because of lack of toxicity at the doses studied. The long radioactivity retention in tumors suggests that isotopes with a long half-life may have a therapeutic advantage, based on calculated dose delivery to tumor versus normal tissue. Due to the low bone marrow dose, further 125I trials with humanized mAb A33 are warranted, and controlled studies must be conducted to evaluate the combination of radioimmunotherapy and chemotherapy.

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Phase I Study of Combination Chemotherapy Plus Ixazomib in Adults with Relapsed or Refractory Acute Lymphoblastic Leukemia/Lymphoma (ALL)

Blood ◽

10.1182/blood.v128.22.5192.5192 ◽

2016 ◽

Vol 128 (22) ◽

pp. 5192-5192

Author(s):

Ehab Atallah ◽

Laura C Michaelis ◽

Karen B. Carlson ◽

Anita D'Souza ◽

Timothy S. Fenske ◽

...

Keyword(s):

Phase I ◽

Dose Level ◽

Research Funding ◽

Phase I Study ◽

Liver Toxicity ◽

Lymphoblastic Leukemia ◽

Median Number ◽

Adult Patients ◽

Response To Treatment ◽

Grade 5

Abstract Introduction: The outcome of adult patients with relapsed/refractory ALL remains dismal. In pediatric patients with relapsed/refractory ALL, the combination of vincristine, doxorubicin, pegaspargase, dexamethasone (VXLD) and bortezomib yielded significant response rates. Based on those results, this study was designed to test the safety of VXLD combined with the oral proteosome inhibitor Ixazomib in adult patients with relapsed/refractory ALL. Study design: This was a phase I study combining vincristine 1.3 mg/m2 (maximum dose 2 mg) D1, 8, 15, and 22, doxorubicin 60 mg/m2 D1, PEGaspargase 2500 units/m2 (capped at 3750 mg) D2, D15, dexamethasone 10 mg/m2 D1-14, with escalating doses of ixazomib. Ixazomib dose was started at 2.3 mg D1, 8, and 15 aiming to increase the dose to 4 mg. Results: Five patients were enrolled on the study between 10/1/13 and 2/26/16, prior to study termination. The median age was 49 years and 3 were female. Median number of prior regimens was 2 (range 2-3). At dose level one, 3 patients were enrolled. Of those patients, one developed grade 5 liver toxicity. That patient achieved complete remission, but died secondary to hyperbilirubinemia and liver failure. One patient developed grade 4 hyperbilirubinemia, did not respond to therapy and died from disease progression. The third patient developed transient grade 3 hyperbilirubinemia, had no response to treatment and went on to receive other therapies. Hepatic toxicities were attributed to pegaspargase. Based on that, the protocol was amended to remove pegaspargase (VXD + Ixazomib). Two patients were enrolled on dose level one (2.3 mg). One patient developed grade 5 infection. Due to increased toxicity in this population, the study was terminated. Conclusion: In our experience, VXLD and VXD were poorly tolerated in adult patients with relapsed/refractory ALL. Ixazomib should be studied with other chemotherapy combinations in adults with relapsed/refractory ALL. Table Table. Disclosures Atallah: Incyte: Consultancy; CTI biopharma: Consultancy; Novartis: Consultancy; BMS: Consultancy; Pfizer: Other: Grant review; Takeda: Research Funding; Ariad: Honoraria. Michaelis:Pfizer: Equity Ownership; Cellgene Corporation: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte Corporation: Consultancy, Honoraria. Hamadani:Takeda: Research Funding. Parameswaran:Takeda: Consultancy.

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