A phase I study of sunitinib in combination with sirolimus in adults with advanced refractory malignancies

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 3554-3554
Author(s):  
J. Li ◽  
H. Kluger ◽  
M. W. Saif ◽  
J. R. Murren ◽  
J. J. Lee ◽  
...  
Keyword(s):  
Dose Level ◽  
Dose Escalation ◽  
Tyrosine Kinases ◽  
Dose Schedule ◽  
Molecule Inhibitor ◽  
Hand Foot Syndrome ◽  
Ecog Ps ◽  
Dose Levels ◽  
Anti Tumor Activity ◽  
Multiple Receptor

3554 Background: Sirolimus, a commercially available oral mTOR inhibitor, may complement the anti-angiogenic and anti-tumor activity of sunitinib, an oral small molecule inhibitor of multiple receptor tyrosine kinases (RTKs), by vertical disruption of VEGFr signaling, by reducing the compensatory production of VEGF in sunitinib-treated patients, and also by directly inhibiting tumor cell proliferation. Methods: Sunitinib was given at 50 mg daily (d) x 28 q6w. The dose of sirolimus was escalated in cohorts of 3–6 beginning at 4 mg weekly until the MTD was determined. The first cohort received sunitinib alone 50mg d x 14 followed by 14 days off in cycle #1. After the 4mg sirolimus dose cohorts, sunitinib dose was reduced in subsequent cohorts to 37.5mg, and dose escalation of sirolimus was re-initiated at 4mg. Results: 18 patients (pts) with ECOG PS <2 were enrolled, median age 57yo (r:24–76), M:F: 11:7. Median # of prior treatments (Rx): 2(r:0–5), 6 had no prior systemic Rx. Disease primary sites: GI-5 (28%), renal cell- 4 (22%), melanoma-2, soft tissue sarcoma (STS)-2, adenoca unknown 10-2, breast-1, H&N-1, NSCLC-1. At the 50/4 dose level, 4 of 8 required dose reduction (DR) or early discontinuation (ED) of Rx in cycle #1. At the 37.5/4 and 37.5/8 dose levels, 3/9 required DR or ED in cycle #1 or starting cycle #2. Several pts able to complete 1–2 cycles at full dose had significant toxicities including fatigue and hand-foot syndrome. 1 pt developed interstitial pneumonitis, 1 pt died on day 8 due to progressive disease. Four pts received >4 cycles (5-STS, 5-renal papillary, 13-neuroendocrine pancreas, 17-renal clear cell). Among 16 pts undergoing restaging, there was no CR or PR. 5 other pts demonstrated transient central necrosis or size reduction in some tumors. There was no apparent PK interaction at the 4mg sirolimus dose level, and no clear effect on sunitinib-induced increase in circulating VEGF levels. Conclusions: Toxicity precluded dose escalation of weekly sirolimus in combination with a standard sunitinib dose/schedule. These results suggest caution when combining targeted agents lacking specificity for tumor signaling or vasculature. [Table: see text]

First-in-human study of the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of PF-00299804, a small molecule irreversible panHER inhibitor in patients with advanced cancer

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 3599-3599 ◽  
Author(s):  
J. H. Schellens ◽  
C. D. Britten ◽  
D. R. Camidge ◽  
D. Boss ◽  
S. Wong ◽  
...  
Keyword(s):  
Small Molecule ◽  
Tyrosine Kinases ◽  
Human Study ◽  
Xenograft Model ◽  
Tumor Growth Inhibition ◽  
Her Family ◽  
Molecule Inhibitor ◽  
Hand Foot Syndrome ◽  
Fdg Pet Ct ◽  
Dose Levels

3599 Background: There are scientific rationale for inhibitors which provide combined and irreversible blockade of HER family members. PF-00299804 is an orally available, potent, irreversible small molecule inhibitor of the HER tyrosine kinases. Methods: The safety, tolerability, PK, PD, and efficacy of PF-00299804 administered orally once daily in 3-week cycles were assessed in patients with advanced solid tumors using an accelerated dose-escalation design. Safety assessments included adverse event (AE), laboratory, ECG, and LVEF assessments. PK parameters were determined after a single lead-in dose and on Day 14 by non-compartmental techniques. PD measures included assessment of HER-related signaling pathways via IHC analyses of serial skin and, in some patients, tumor biopsies. Serial 18F-FDG- PET/CT has been performed on a subset of patients with scans being classified according to modified EORTC criteria by a central reader. Results: 32 pts have been treated across 8 sequential dose levels ranging from 0.5 to 60 mg. The most common AEs were diarrhea, fatigue, nausea, and rash. 3/6 patients at 60 mg experienced a DLT [hand-foot syndrome (1), dehydration related to diarrhea(1), mucositis(1)]. Cmax and AUC of PF-00299804 increased with dose in an approximately proportional manner. Accumulation ranged from 3.3 to 6.8, suggesting a terminal t1/2>24 h. At the 30 mg dose level, mean Day 14 drug concentration was above the predicted efficacious concentration for tumor growth inhibition based on A431 xenograft model. Of 7 sets of PET data evaluated thus far, partial responses (PR) have been observed in 2 patients. A PR as assessed using RECIST criteria has been reported in 1 of 2 patients with advanced refractory NSCLC treated to date. Conclusions: Daily administration of PF-00299804 across many dose levels appears safe and tolerable. Diarrhea, fatigue, nausea, and rash are the most frequent AEs. Evaluation of 45 mg/d as the potential MTD is ongoing. Systemic exposures at doses = 30 mg exceed the threshold for efficacy as predicted from preclinical studies. Clinical and biological activity of PF-00299804 was observed including a PR in 1 of 2 patients with advanced refractory NSCLC. No significant financial relationships to disclose.

A dose-escalation study of oxaliplatin/capecitabine/irinotecan (XELOXIRI) and bevacizumab (bev) as a first-line therapy for patients with metastatic colorectal cancer.

2014 ◽  
Vol 32 (3_suppl) ◽  
pp. 612-612
Author(s):  
Yasushi Sato ◽  
Hiroyuki Ohnuma ◽  
Masahiro Hirakawa ◽  
Minoru Takahashi ◽  
Takahiro Osuga ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Dose Level ◽  
Dose Escalation ◽  
Response Rate ◽  
Recommended Dose ◽  
Dose Escalation Study ◽  
First Line Therapy ◽  
Ecog Ps ◽  
Dose Levels

612 Background: In a recent study by Loupakis, F. et al. (ASCO-GI 2013), a FOLFOXIRI and bevacizumab regimen showed promising activity and conversion rate in patients (pts) with metastatic colorectal cancer (mCRC). In order to evaluate a treatment regimen that was easier to administer, we conducted a dose-escalation study to determine the recommended dose (RD) of irinotecan (IRI) in combination with oxaliplatin and capecitabine and bevacizumab (XELOXIRI/bev) in pts with mCRC. Methods: Pts were eligible if they had mCRC (liver and/or other metastases), ECOG PS 0-1, were either negative or heterozygous for UGT1A1*6 or UGT1A1*28 and were not pretreated for metastatic disease. Treatment consisted of oxaliplatin (100 mg/m2 day 1), capecitabine (1700 mg/m2/day from day 2 to 15), IRI (100,120,150 mg/m2 for dose levels 1, 2, or 3, day 1) and bev (7.5 mg/kg, day 1), repeated every 3 weeks. The dose of IRI was escalated if dose limiting toxicities (DLT) were absent in the first three pts per cohort, or if <2 DLTs were observed in six pts. If the MTD was not reached at the planned dose levels, the RD of IRI was defined as 150mg/m2, which is the maximum dosage approved for use in Japan. Results: 12 pts (F/M: 4/8, median age: 58 years, PS 0/1: 11/1) received a median of 6 cycles of therapy (range 2-12). The DLT was grade 4 neutropenia, which was observed in 1 of 6 pts at dose level 2. MTD was not reached at dose level 3. Therefore, the RD of IRI was defined as 150 mg/m2. Most common grade ≥ 3 toxicities were neutropenia (58.3%), anemia (16.6 %), diarrhea (8.3%), and febrile neutropenia (8.3 %). The response rate was 83.3%(95% CI 60-89), including 1 CR, 9 PRs. The disease control rate was 100%(95% CI 80-100). At a median follow-up of 8 months, median PFS was 15 months and median OS was not yet reached. Conclusions: XELOXIRI/bev is a feasible regimen; neutropenia was the DLT; recommended dose of IRI is 150 mg/m². The observed response rate of 83.3% is very promising and warrants further investigation. Clinical trial information: UMIN000005440.

scholarly journals 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 ◽  
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.

A Multicenter Phase I/II Trial Evaluating the Safety and Efficacy of Lenalidomide [Revlimidä (R), CC-5013] in Combination with Doxorubicin and Dexamethasone (RAD) in Patients with Relapsed or Refractory Multiple Myeloma.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 5136-5136 ◽  
Author(s):  
C. Gerecke ◽  
S. Knop ◽  
M.S. Topp ◽  
S. Kotkiewitz ◽  
H. Gollasch ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Phase I ◽  
Dose Level ◽  
Fixed Dose ◽  
Severe Toxicity ◽  
Refractory Multiple Myeloma ◽  
Dose Levels ◽  
Anti Tumor Activity ◽  
Level 2 ◽  
Dose Limiting Toxicity

Abstract Introdution: Lenalidomide (Revlimid™) is Celgene’s lead clinical compound in a new group of drugs called IMiDs, which have immunomodularory properties. The drug has been evaluated in phase-I, II, and III clinical trials for the treatment of multiple myeloma (MM). Lenalidomide shows substantial anti-tumor activity in patients with refractory or relapsed MM and significantly prolongs time to tumor progression (TTP) compared to standard therapy in these patients. Lenalidomide was well tolerated in these trials, the only dose limiting toxicity in a phase-I trial was myelosuppression. In order to further improve therapeutic efficacy and to overcome drug resistance we are currently evaluating Lenalidomide (Revlimid™) in combination with doxorubicin and dexamethasone (RAD) for the treatment of patients with refracrory or relapsed MM in a phase-I/II trial. Methods: Patients with relapsed or refractory multiple myeloma recieve a fixed dose of either 10 mg or 15 mg Revlimid Revlimid™ given daily for 21 days (d 1–21) in combination with doxorubicin (adriamycin) and dexamethasone, to be repeated on day 29. Three dose levels of doxorubicin (adramycin) are planned: 4 mg/m2 day 1–4, 6 mg/m2 day 1–4 and 9 mg/m2 day 1–4. 40 mg dexamethasone is given orally day 1–4 and day 17–20 at a fixed dose. 3– 6 cycles are applicated unless severe toxicity or disease progression occurs. Results: RAD treatment was well tolerated at dose level 1 and dose level 2. Therefore, current dose escalation is continued. All patients treated at the first two dose levels (6/6) responded to RAD treatment. Further updated results on this trial will be presented.

Clinical Activity of a Novel Multiple Tyrosine Kinase and Aurora Kinase Inhibitor, ENMD-2076, Against Multiple Myeloma: Interim Phase I Trial Results

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1957-1957 ◽  
Author(s):  
Sherif Farag ◽  
Shuhong Zhang ◽  
Attaya Suvannasankha ◽  
Jing Liang ◽  
Robyn O'Bryant ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Phase I ◽  
Dose Level ◽  
Dose Escalation ◽  
Phase I Clinical Trial ◽  
M Protein ◽  
High Dose ◽  
Significant Activity ◽  
Dose Levels ◽  
Asymptomatic Elevation

Abstract Abstract 1957 Background: Despite recent improvements, MM remains incurable, indicating the need for continued investigation of novel agents. ENMD-2076 is a novel, orally active molecule that has been shown to have significant activity against Aurora and multiple receptor tyrosine kinases. Recently, we demonstrated that ENMD-2076 has significant pre-clinical in vitro and in vivo activity against MM cell lines and primary myeloma cells (Wang et al., Br J Haematol, 2010). Furthermore, ENMD-2076 inhibited critical pathways for MM cell survival and proliferation, including PI3K/AKT pathway with downregulation of survivin and XIAP, and Aurora A and B kinases, inducing G2/M cell cycle arrest, angiogenesis, and the FGFR3 pathway. We present the interim results of a phase I clinical trial of ENMD-2076 in patients with relapsed and refractory MM. Methods: An open label, single agent, dose-escalation dose safety and tolerability trial of ENMD-2076 is currently conducted in heavily pre-treated, relapsed and refractory MM patients who have previously failed standard therapy. Using a 3+3 design, dose escalation with ENMD-2076 is currently being studied at the doses: 150, 225, 325, 400 mg PO daily in 28 day cycles. Patients receive 28-day cycles according to safety and tolerability and absence of progression. Pharmacokinetics and pharmacodynamic studies, including effect on phosphorylated histone 3 (pH3) in purified bone marrow MM cells, effect on the PI3K pathway in peripheral blood mononuclear cells (PBMC), and circulating endothelial cell precursors are being investigated. Results: Currently, dose-escalation for the first three dose levels has been completed. Nine patients of median age 54 (range, 48–76) years were treated. There were 5 males and 4 females. The median number of prior regimens was 3 (range, 2–5), with 8 patients having failed high-dose melphalan and autologous stem cell transplantation. The most commonly observed toxicities included grades 1–2 anorexia (n=2), nausea (n=2), diarrhea (n=3), fatigue (n=3), asymptomatic elevation of amylase (n=3) and lipase (n=1), leucopenia (n=1), and heavy proteinuria (n=1). Grades 3 toxicities included hypertension (n=1), asymptomatic elevation of lipase (n=2), and thrombocytopenia (n=1). No dose-limiting toxicity was observed with all toxicities resolving promptly upon interruption or discontinuation of dosing. All patients treated on dose level 1 had progression of disease on treatment, 1 patient in dose level 2 had stabilization of disease, and 2 patients on dose level 3 had stable disease although with 21% and 19% reduction in serum M-protein after the first cycle. Significant increases in pH3 in MM cells were observed in 4 of 5 patients tested in dose levels 2 and 3. p-STAT3 and pGSK-beta were downregulated in PBMC in one patient, who also had a 19% reduction in M-protein. Conclusion: In the ongoing phase I clinical trial, ENMD-2076 appears safe and well –tolerated at the doses tested to date. Additional schedules are under investigation based on tolerability and correlative analyses. ENMD-2076 may hold promise as a treatment for MM and further study is warranted. Disclosures: Farag: EntreMed, Inc: Research Funding. Bray:EntreMed, Inc.: Employment. Sidor:EntreMed, Inc: Employment.

Phase I, safety, pharmacokinetic and biomarker study of BAY 57–9352, an oral VEGFR-2 inhibitor, in a continuous schedule in patients with advanced solid tumors

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 3040-3040
Author(s):  
H. Gelderblom ◽  
J. Verweij ◽  
N. Steeghs ◽  
A. Van Erkel ◽  
L. Van Doorn ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Dose Level ◽  
Tyrosine Kinases ◽  
Competitive Inhibitor ◽  
Advanced Solid Tumors ◽  
Tumor Patient ◽  
Contrast Enhanced ◽  
Ca Antagonist ◽  
Grade 3 ◽  
Dose Levels

3040 Background: BAY 57–9352 is a potent competitive inhibitor of the VEGFR-2 (IC50: 6 nM), VEGFR-3 (IC50: 4 nM), PDGFR-β and c-KIT tyrosine kinases. BAY 57–9352 showed tumor efficacy in colon, breast, pancreatic and NSCLC models. Methods: Patients with advanced solid tumors received oral BAY 57–9352 on a continuous basis, in escalating doses. One cycle was defined as 21 days of treatment. Extensive PK and PD (dynamic contrast-enhanced MRI [DCE-MRI]) evaluations were performed. Plasma biomarkers (e.g. VEGF)were also evaluated. Results: Forty patients (median 54 yrs) were enrolled at seven dose levels from 20 mg solution once daily to1500 mg twice daily (bid; 150 mg tablets) for a total of 169 cycles (range 1–17). The most frequent drug-related adverse events were nausea, hypertension, headache, vomiting, hoarseness, rash, dry skin and anorexia. One patient treated at 600 mg bid had a dose-limiting toxicity defined by an increase from grade 2 to 3 hypertension, despite the addition of an ACE-inhibitor and Ca-antagonist on day 8 of cycle 2. Another patient at that same dose level and also on day 8 cycle 2, had grade 3 AST/ALT increase, however this was not assessed as dose-limiting. Both patients continued treatment after dose reductions. Treatment was well tolerated, even at the highest dose levels. One patient with a hemangio-endothelioma (600 mg bid) had a clinical response and one desmoid tumor patient (900 mg bid) had a 53% reduction in tumor volume. BAY 57–9352 AUC increased dose proportionally up to 900 mg bid. The target AUC, based on animal models (5 mg × h/L) was reached in all patients at 900 mg bid. Dose levels exceeding 900 mg bid had similar plasma VEGF biomarker levels. Conclusions: BAY 57–9352 was well tolerated in doses up to 1500 mg bid. Based on safety, PK, PD and biomarker assessments, the recommended dose level is 900 mg bid. A 300 mg tablet is being tested for patient convenience. Combination chemotherapy studies have been started. [Table: see text]

Pharmacodynamic-guided, modified continuous reassessment method (mCRM)-based, dose finding study of rapamycin in adult patients with solid tumors

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 3020-3020 ◽  
Author(s):  
A. Jimeno ◽  
P. Kulesza ◽  
G. Cusatis ◽  
A. Howard ◽  
Y. Khan ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Dose Level ◽  
Dose Escalation ◽  
Dose Finding ◽  
Phase I Trials ◽  
Dose Selection ◽  
Normal Tissues ◽  
Tumor Biopsies ◽  
Dose Levels

3020 Background: Pharmacodynamic (PD) studies, using either surrogate or tumor tissues, are frequently incorporated in Phase I trials. However, it has been less common to base dose selection, the primary endpoint in Phase I trials, in PD effects. We conducted a PD-based dose selection study with rapamycin (Rap). Methods: We used the modified continuous reassessment method (mCRM), a computer-based dose escalation algorithm, and adapted the logit function from its classic toxicity-based input data to a PD-based input. We coupled this design to a Phase I trial of Rap with 2 parts: a dose estimation phase where PD endpoints are measured in normal tissues and a confirmation phase where tumor tissue is assessed. Patients (pts) had solid tumors refractory to standard therapy. Rap was given starting at 2 mg/day continuously in 3-pt cohorts. The PD endpoint was pP70S6K in skin and tumor. Biopsies were done on days 0 and 28 of cycle 1, and a PD effect was defined as ≥ 80% inhibition from baseline. The first 2 dose levels (2 and 3 mgs) were evaluated before implementing the mCRM. The data was then fed to the computer that based on the PD effect calculated the next dose level. The mCRM was set so escalation continued until a dose level elicited a PD effect and the mCRM assigned the same dose to 8 consecutive pts, at which point the effect of that dose will be confirmed in tumor biopsies. Other correlates were PET-CT and pharmacokinetics. Results: Ten pts were enrolled at doses of 2 mg (n = 4), 3 mg (n = 3) and 6 mg (n = 3). Toxicity was anemia (4 G1, 1 G2), leucopenia (1 G1, 2 G2), low ANC (2 G2), hyperglycemia (2 G1, 1 G2), hyperlipidemia (4 G1), and mucositis (1 G1, 1 G2). PD responses were seen in 2 and 1 pt at 2 and 3 mg dose levels. Input of data to the mCRM selected a dose of 6 mg for the third cohort, where PD effect was seen in 1 pt, and thus a fourth dose around 9 mg will be tested. No responses by RECIST occurred, but 2 pts had a response by PET. The PK was consistent with prior data (t1/2 24.6 ± 10.2 h, CL 31.4 ± 12.0 L/h, vol of distribution 235 ± 65 L), and exposure increased with dose. Steady-state concentration were in the 5–20 nM range. Conclusions: mCRM-based dose escalation based on real-time PD assessment is feasible and permits the exploitation of PD effects for dose selection in a rational manner. No significant financial relationships to disclose.

A phase I dose escalation study of pemetrexed in patients with advanced head and neck squamous cell cancer (HNSCC)

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 6055-6055 ◽  
Author(s):  
P. H. Morrow ◽  
B. S. Glisson ◽  
L. E. Ginsberg ◽  
S. M. Lippman ◽  
M. S. Kies ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Escalation ◽  
Cell Cancer ◽  
Maximum Tolerated Dose ◽  
Vitamin Supplementation ◽  
Dose Escalation Study ◽  
Grade 3 ◽  
Ecog Ps ◽  
Dose Levels ◽  
Neck Squamous Cell Cancer

6055 Background: Despite recent advances in therapy, patients (pts) with recurrent or metastatic HNSCC continue to demonstrate a poor median survival. In these pts, early trials with pemetrexed, a novel antimetabolite that acts upon several enzymes involved in pyrimidine and purine synthesis, have demonstrated promising efficacy and tolerability. Prior studies found that the administration of oral dexamethasone with pemetrexed reduced the incidence of skin rash. Later, vitamin supplementation (B12 and folic acid), given in addition to the dexamethasone, further diminished side effects. However, no trial has yet evaluated the appropriate steroid dose and its relation to the dosing of pemetrexed, in the setting of vitamin supplementation. We conducted a phase I trial to determine the maximum tolerated dose, toxicity, and preliminary efficacy of pemetrexed when given with different schedules of, or in the absence of, dexamethasone in pts with advanced HNSCC who had been treated with at least one or more chemotherapy regimens. Methods: Eligible pts had metastatic or recurrent HNSCC, prior treatment with one or more chemotherapy regimens, ECOG PS =2, and life expectancy >3 months. A conventional algorithm-based dose escalation design was applied, with three predefined dose levels (DL) of pemetrexed (500 mg/m2, 600 mg/m2, and 700 mg/m2) within each schedule of dexamethasone (none, 20 mg IV on day 1, and 4 mg orally bid for 3 days). Results: A total of 23 pts have been enrolled; 18 pts were evaluable. Median age was 57 years (range 47–82). Median ECOG PS was 1 (range 0–2), and 75% of pts were male. Number of prior chemotherapy regimens were as follows: 1 (40%), 2 (35%), 3 (15%), and 4 (10%). Preliminary data demonstrated only 2 treatment-related adverse events that were grade 3 or greater: anemia (DL1) and pneumonia (DL 1). In all, 13 pts have received pemetrexed with less than standard recommended dexamethasone dosing (none or IV), including 7 pts who received no dexamethasone. Of the 18 evaluable pts, 1 pt had a partial response and 2 pts had stable disease. Conclusions: This represents the first study that demonstrates that steroids may not be required as premedication with pemetrexed. Due to the limited toxicity observed, trial enrollment continues with dose escalation. [Table: see text]

scholarly journals Total Body Irradiation (TBI) Dose Escalation Decreases Risk of Progression and Graft Rejection after Hematopoietic Cell Transplantation with Nonmyeloablative Conditioning for Myelodysplastic Syndrome (MDS) or Myeloproliferative Neoplasms (MPN)

Blood ◽  
2017 ◽  
Vol 130 (Suppl_1) ◽  
pp. 908-908
Author(s):  
Federico Monaco ◽  
Bart L. Scott ◽  
Thomas Chauncey ◽  
Finn Petersen ◽  
Barry E. Storer ◽  
...  
Keyword(s):  
High Risk ◽  
Dose Level ◽  
Primary Endpoint ◽  
Dose Escalation ◽  
Cumulative Incidence ◽  
Hematopoietic Cell Transplantation ◽  
Myeloproliferative Neoplasms ◽  
Advisory Board ◽  
Level 3 ◽  
Dose Levels

Abstract Purpose A nonmyeloablative (NMA) regimen of fludarabine and 200cGy TBI combined with post-grafting immunosuppression with mycophenolate mofetil (MMF) and a calcineurin inhibitor allows for allogeneic hematopoietic cell transplantation (HCT) from HLA-matched related or unrelated donors in older patients and those with comorbidities affected by myelodysplastic syndrome (MDS) or myeloproliferative neoplasms (MPN). Results of phase I/II studies in patients with chronic myelomonocytic leukemia (CMML) or MDS/MPN have been disappointing, however, due to high incidences of relapse or graft failure (together termed HCT-failure). We hypothesized that escalating the TBI dose may decrease relapse and ensure engraftment. We performed a phase I/II TBI dose-escalation trial and compared the rates of HCT-failure. Methods This was a study conducted at three transplant centers. Patients ages 50-75 or &lt;50 (median age 66) years with high risk comorbidities (Table 1) received NMA conditioning followed by HCT, with TBI dose escalation: Arm A - patients with MPN or low-risk MDS (RA-RARS-RCMD) or PNHArm B - patients with high-risk MDS (RAEB-1) or CMML Patients with MDS/MPN could not have received myelosuppressive chemotherapy; patients with CMML who had progressed could have received myelosuppressive chemotherapy before HCT to reduce marrow blasts to less than 5%. Patients were enrolled in groups of 6; dose escalation rules were imposed for HCT failure &gt;20% before day 200 on Arms A and B. Stopping rules were imposed for nonrelapse mortality (NRM) at day 200 of &gt;25% in Arm A and &gt;35% in Arm B. The TBI dose levels were: Level 1: 300cGyLevel 2: 400cGyLevel 3: 450cGy All patients received fludarabine 30/m2/day IV x3 days on days -4 to -2. TBI was administered on day 0 followed by infusion of G-CSF mobilized PBSC from HLA-matched related (n=30) or unrelated (n=47) donors. Post-grafting immunosuppression with MMF and cyclosporine was administered. The primary endpoint was a decrease in the incidence of day200 HCT-failure to &lt;20%; secondary endpoints included overall survival (OS), progression-free survival (PFS), relapse incidence (RI) and NRM. Results The study enrolled 77 patients with 36 patients in Arm A and 41 patients in Arm B. Median follow-up is 56.3 months among surviving patients. The primary endpoint (Figure 1) was reached on Arm A at dose level 1 (300cGy TBI) with a cumulative incidence of day200 HCT-failure of 11%. The primary endpoint was not reached in Arm B at dose levels 1 and 2, with dose escalation being triggered at 12 and 5 patients respectively. The endpoint was reached on dose level 3 (450cGy) with a cumulative incidence of day200 HCT-failure of 9%. See Table 2 and Figures 2-5 for OS, PFS, RI and NRM. Cumulative incidence of grades III-IV acute graft-versus-host (aGvHD) by day100 was 17% in Arm A, 12% in Arm B for dose levels 1-2, and 9% in Arm B for dose level 3. Chronic graft-versus-host (cGvHD) cumulative incidence at 1year was 44% in Arm A, 35% in Arm B for dose levels 1-2 and 29% in Arm B for dose level 3. Regarding chimerism analysis, no statistically significant differences were seen among the different arms (Figure 6). Summary and Conclusions In Group A (MPN / low-risk MDS), increasing the TBI dose from 200cGy to 300cGy reduced the day200 HCT-failure rate from 31% in previous trials to 11%. As a result, the OS and PFS was 61% and 58%, respectively, at 2 years. Similarly, for Group B (high-risk MDS / CMML), the day200 HCT-failure rate was reduced from 58% in previous trials to 9% when 450cGy was used. This resulted in an OS and PFS of 37% and 33%, respectively, at 2 years. TBI doses of 300cGy and 400cGy were insufficient to reduce HCT-failure in this high risk group. In conclusion, increasing the TBI dose can lead to a higher success rate in this setting of nonmyeloablative conditioning by reducing both relapse and rejection. Further studies are necessary to decrease nonrelapse mortality, especially among patients affected by high-risk disease. Current trials using targeted radioimmunotherapy are currently being investigated towards this end. Disclosures Flowers: Pharmacyclics: Consultancy. Maloney: Kite Pharmaceuticals: Other: Advisory board; Celgene: Other: Advisory board; Juno Theraapeutics: Other: Advisory board, Patents & Royalties, Research Funding; Roche/Genetech: Other: Advisory board.

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