Phase I study of a novel, pharmacokinetically derived schedule of flavopiridol in acute leukemias: Clinical efficacy including hyperacute tumor lysis, pharmacokinetics, and pharmacodynamics

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 6568-6568
Author(s):  
W. Blum ◽  
R. B. Klisovic ◽  
C. Kefauver ◽  
A. Johnson ◽  
M. Phelps ◽  
...  
Keyword(s):  
Phase I ◽  
Kinase Inhibitor ◽  
Single Agent ◽  
Calf Serum ◽  
Clinical Activity ◽  
Acute Leukemias ◽  
Tumor Lysis ◽  
Optimal Dosing ◽  
Dose Levels

6568 Background: Flavopiridol is a cyclin dependent kinase inhibitor with in vitro activity in many cancer cell lines. However, phase I/II studies of either 24 or 72-hour continuous infusion schedules demonstrated no significant clinical activity. Discordant binding of flavopiridol to human plasma proteins as compared to fetal calf serum prompted us to perform pharmacokinetic modeling studies which suggested that optimal dosing would be a 30 min IV bolus followed by 4 hr IV infusion. With this schedule, our group has observed impressive clinical activity in refractory CLL. Methods: We intensified this schedule for relapsed or refractory adult AML and ALL patients (pts) to administer an IV bolus over 30 min followed by an infusion over 4 hrs on 3 consecutive days in a phase I trial. Results: To date, 10 pts have been treated at 2 dose levels. Pts had relapsed/refractory AML (N=6) or ALL (N=4) and were 25–77 yrs old. 4 pts received flavopiridol at 20 mg/m2 IV bolus and 30 mg/m2 infusion; 6 received 30 mg/m2 bolus followed by 35 mg/m2 infusion. The most significant toxicity was tumor lysis; treatment was well tolerated, and toxicities were similar to those previously reported by our group with the single day dosing schedule used in CLL. Plasma levels were 1–2 μM during the infusion (N=7) and declined with a terminal half life comparable to that previously reported with a 72 hr infusion. Significant anti-leukemic activity was seen in 5/7 evaluable pts at both dose levels. Tumor lysis was seen in both ALL and AML (see table ). Downregulation of Mcl-1 protein by immunoblotting was seen in 2/3 pts tested to date. Conclusions: Single agent flavopiridol given with this novel, pharmacologically modeled schedule has clinical activity in pts with relapsed/refractory ALL and AML. Further study in acute leukemia using this schedule is warranted; dose escalation to the current trial is ongoing. (NCI U01 CA 76576–05) [Table: see text] No significant financial relationships to disclose.

Combination of Sorafenib, Idarubicin, and Cytarabine Has a High Response Rate in Patients with Newly Diagnosed Acute Myeloid Leukemia (AML) Younger Than 65 Years

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 768-768 ◽  
Author(s):  
Farhad Ravandi ◽  
Jorge Cortes ◽  
Stefan Faderl ◽  
Guillermo Garcia-Manero ◽  
Susan O’Brien ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Phase I ◽  
Cell Lines ◽  
Phase Ii ◽  
Kinase Inhibitor ◽  
Single Agent ◽  
High Response Rate ◽  
Clinical Activity ◽  
Mutation Burden

Abstract Background: Sorafenib is an orally active multi-kinase inhibitor with potent activity against the Raf/ERK/MEK pathway, VEGFR, PDGFR-β, and c-KIT. In vitro, it has growth-inhibitory effects in several AML cell lines with or without constitutive activation of ERK signaling. Sorafenib selectively induces cell growth arrest and apoptosis in FLT3-mutant human AML cell lines at nM concentrations. In a phase I study of single agent sorafenib in patients (pts) with AML escalating doses were well tolerated with no myelosuppression and with significant clinical activity predominantly (but not exclusively) in FLT3 mutated pts. Methods: This study was conducted to determine the tolerability and efficacy of combination of sorafenib with cytarabine 1.5 g/m2 iv over 24 hours daily × 4 (× 3 for pts over 60) and idarubicin 12 mg/m2 iv daily × 3. In the phase I portion of study, pts with relapsed AML were treated with escalating doses of sorafenib po (400 mg qod, 400 mg daily and 400 mg bid) for 7 days during induction, and 400 mg bid was established as a safe dose for phase II evaluation. Pts achieving CR receive up to 5 courses of consolidation with idarubicin 8 mg/m2 iv daily × 2 and cytarabine 0.75 g/m2 iv daily × 3 in addition to continuous sorafenib 400 mg po bid for up to 28 days per cycle. Maintenance with sorafenib 400 mg bid would continue for up to a year after consolidation. Results: Ten pts (median age 34 years, range 21–58) with relapsed AML (median prior therapy 2, range 1–6) were treated on the phase I portion. Seven had FLT3-ITD mutation (5 with high mutation burden, 2 with low), and 3 were negative. Four achieved CR, and 6 failed. In the phase II portion, 30 pts (including 8 with FLT3-ITD and 2 with FLT3-TKD) have been treated. Median age is 53 years (range 18 – 65) Cytogenetics were diploid in 13, +8 in 3, −5/−7 in 3, t(9;11) in 1, miscellaneous in 6, and unavailable in 4. The median presentation WBC was 4.6 × 109/L (range 1.5 –122.7 × 109/L). FLT3 mutation burden was low in blasts from 4 pts, and high in 6). Five pts were FLT3-ITD+/NPM1-. Among 25 evaluable pts, 22 (88%) have achieved CR (n=19), or CRi (n=3); 1 achieved PR, 1 died at induction from pneumonia, 1 was resistant; 5 pts are too early. The regimen is well tolerated and grade 3 adverse events thought to be possibly related to the study combination have included elevation of transaminases (3), hyperbilirubinemia (4), small bowel obstruction (1), diarrhea (2), rash (2), pericarditis (1), elevated creatinine (1), and atrial fibrillation (1). Median follow-up is 8 weeks (range, 1 – 28) with the probability of survival at 6 months of 87%; 2 pts have relapsed with CR durations of 2 and 3 months. Samples from 8 pts were studied prior to and 24–48 hours post sorafenib administration, and prior to chemotherapy. In six pts (75%), sorafenib alone induced apoptosis in peripheral blood blasts and in CD33/CD34 positive leukemia progenitor cells as determined by flow cytometry. Expression of phospho-ERK (pERK) was detectable by flow cytometry in 5 out of 7 samples tested at baseline; 24-hour exposure to sorafenib resulted in >50% downregulation of pERK in 3 of the 5 samples. Plasma inhibitory assay was performed using day 7 samples from 10 pts; mutant FLT3 was suppressed by all samples with 5-fold more potent suppression against mutant versus wildtype FLT3. Conclusions: Combination of sorafenib with idarubicin and cytarabine is safe and has a high CR rate in frontline therapy of younger pts with AML. Correlative studies confirm potent activity of sorafenib against ERK and FLT3 signaling.

Flavopiridol Administered as a Pharmacologically-Derived Schedule Demonstrates Marked Clinical Activity in Refractory, Genetically High Risk, Chronic Lymphocytic Leukemia (CLL).

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 341-341 ◽  
Author(s):  
John C. Byrd ◽  
Thomas S. Lin ◽  
James T. Dalton ◽  
Di Wu ◽  
Beth Fischer ◽  
...  
Keyword(s):  
High Risk ◽  
Phase I ◽  
Opportunistic Infections ◽  
Single Agent ◽  
Tumor Lysis Syndrome ◽  
Calf Serum ◽  
Potassium Phosphate ◽  
Lymphocytic Leukemia ◽  
Clinical Activity ◽  
Tumor Lysis

Abstract Flavopiridol is a broad cyclin dependent kinase inhibitor that induces p53/IL4 independent apoptosis in CLL cells. Despite potent pre-clinical activity, phase I/II studies of both a 24 and 72-hour continuous IV (CI) schedule demonstrated no activity in CLL or other cancers. Discordant binding of flavopiridol to human plasma proteins as compared to fetal calf serum prompted us to perform pharmacokinetic modeling from the Aventis-sponsored CI studies. This suggested optimal dosing would be a 30-minute IV bolus followed by 4-hour infusion. We report a mature phase I dose escalation study of flavopiridol with this schedule. We enrolled 23 pts (median age 61, range 44–84, 8 female) previously treated for CLL (median prior therapies 3, range 2–13) . At study entry, 21 pts had no response to their last therapy, 9 had intermediate risk disease, and 14 were stage III/IV. Pts received 50% of the flavopiridol dose IV over 30 minutes, the remaining 50% followed over 4 hours. This was repeated weekly 4 times on a 6-week cycle. Six pts in cohort 1 received 60 mg/m2/dose with 1 dose limiting toxicity (DLT, neutropenic fever) and 3 pts in cohort 2 received 80 mg/m2/dose. The maximally tolerated dose was exceeded in cohort 2. Acute tumor lysis syndrome (TLS) following the first flavopiridol dose was the DLT. One pt developed TLS that was controlled with aggressive medical management. The 2nd pt with TLS died with hyperkalemia before dialysis could be initiated, and on autopsy had extensive apoptosis/necrosis of diffuse intra-abdominal lymphadenopathy. No additional pts were treated at this dose, but a 3rd pt previously without TLS at the 80 mg/m2/dose developed TLS on day 1,cycle 2 at the 60 mg/m2 dose. An inpatient management plan to prevent further life-threatening TLS was initiated. We enrolled 14 additional pts. Several pts developed transient tumor lysis upon initial treatment, with increased serum potassium, phosphate, and LDH, but only 1 pt required temporary dialysis. Other manageable toxicities observed included neutropenia, anemia, thrombocytopenia, fatigue, nausea, diarrhea, and anorexia. Twenty-two patients have been followed long enough for NCI 96 response assessment. Nine pts achieved a PR (41%); 7 pts remain in remission (3–11+ months), and 2 pts relapsed at 7 and 12 months, respectively. Of the 9 responding pts, 8 were fludarabine refractory or intolerant, 8 had bulky LN (> 5cm), and 8 had del(11q) [n=6] or del(17p) [n=3] abnormalities. Additionally, opportunistic infections have not been noted to date. Eight of 9 responding pts with enlarged LN had a 50% reduction with the 1st treatment, compared to 2 of 10 who did not ultimately achieve a PR. The AUC of flavopiridol did not increase proportionally with dose, but pharmacologic data support our hypothesis that the clinical activity and toxicity of flavopiridol may be directly related to the Cmax, AUC, and Css. In summary, single agent flavopiridol given with this novel, pharmacologically modeled schedule has significant clinical activity in pts with fludarabine-refractory, genetically high-risk CLL. Further study of flavopiridol in CLL and other B-cell diseases using this pharmacokinetically modeled schedule is warranted.

A phase I study of nilotinib alone and in combination with imatinib (IM) in patients (pts) with imatinib-resistant gastrointestinal stromal tumors (GIST) - Study update

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 10023-10023 ◽  
Author(s):  
M. Von Mehren ◽  
P. Reichardt ◽  
P. G. Casali ◽  
J. Blay ◽  
M. Debiec-Rychter ◽  
...  
Keyword(s):  
Phase I ◽  
Phase I Study ◽  
Kinase Inhibitor ◽  
Progression Free Survival ◽  
Skin Toxicity ◽  
Clinical Activity ◽  
Imatinib Resistant ◽  
Exon 9 ◽  
Exon 11

10023 Background: Nilotinib is a novel tyrosine kinase inhibitor (TKI) targeting KIT, PDGFR, and Bcr-Abl and inhibiting the proliferation of both IM-sensitive and -resistant cells in vitro. We report the results of a phase I study in GIST pts resistant to IM and other TKIs. Methods: Pts with progressive disease received nilotinib alone (400 mg p.o. bid) or escalating doses of nilotinib (200 mg qd, 400 mg qd, or 400 mg bid) in combination with IM (400 mg p.o. bid), or nilotinib 400 mg bid plus IM 400 mg qd. Pharmacokinetic (PK) analyses were performed. Tumor assessments (RECIST) were done every 8 weeks. Baseline samples of 18 GISTs were analyzed for KIT and PDGFR mutations. Results: 53 pts received nilotinib, alone (n=18) or in combination with IM (n=35), for a median of 134 days (range 8 to 430 days). Thirty-nine pts (74%) had failed second-line therapies including sunitinib, AMG-706, dasatinib or RAD001. Most frequent adverse events were grade 1 (17% of pts) or 2 (51% of pts) including: skin toxicity, fatigue, myalgia, headache, abdominal pain, nausea, vomiting, diarrhea, constipation, hyperbilirubinemia and edema. Six pts experienced dose limiting hyperbilirubinemia or skin rash. One pt on nilotinib alone achieved partial response (PR) for > 6 months and 36 pts (68%)-13 on nilotinib alone-, had SD ranging from 6 weeks to > 6 months. Median progression-free survival was 134 days overall and 178 days for pts on nilotinib alone. Genotyping revealed mutations in KIT exon 9 (n=4) or 11 (n=11), and KIT WT (n=3). The single PR occurred in KIT exon 11 mutant GIST following previous adjuvant imatinib and intolerance to imatinib 800 mg. KIT was WT in 2 out of 8 pts with SD > 6 months. Conclusions: Nilotinib, alone and in combination with IM has promising clinical activity in pts with GIST resistant to prior TKIs. Tolerability is acceptable for both nilotinib 400 mg bid, alone and in combination with IM 400 mg qd, which are the recommended doses for future studies. No significant financial relationships to disclose.

Final results of phase I and pharmacokinetic study of SJG-136 administered on a daily x 5 schedule

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e13506-e13506 ◽  
Author(s):  
T. M. Kadia ◽  
S. Faderl ◽  
Z. Estrov ◽  
M. Konopleva ◽  
S. George ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Level ◽  
Performance Status ◽  
Median Number ◽  
Clinical Activity ◽  
Vascular Leak ◽  
Ecog Performance Status ◽  
Acute Leukemias ◽  
Number Of Patients ◽  
Dose Levels

e13506 Background: SJG-136 is a pyrrolobenzodiazepine dimer that forms covalent DNA crosslinks in a sequence-specific manner in the minor groove. In vitro testing demonstrated a broad pattern of antitumor activity in sub-nmol concentrations. A phase I study in patients (pts) with solid tumors revealed clinical activity, defined MTD as 30 mg/m2/d administered on daily x 3 schedule, and confirmed manageable toxicity. Here we report the results of a CTEP-sponsored phase I trial of SJG-136 administered on a daily x 5 schedule in pts with relapsed or refractory (R/R) leukemias. Methods: Previously treated pts with R/R acute leukemias (AML, ALL, high risk MDS, CML blast phase) or R/R CLL with adequate organ function and ECOG performance status of ≤ 2 were eligible for the study. The starting dose level was 6 mcg/m2 given intravenously daily x 5 days on a 21 day cycle. Pts were sequentially enrolled in cohorts of 3 and the dose was escalated in a classic 3+3 schema at the dose levels: 6, 12, 24, and 36 mcg/m2. Repeat courses and intrapatient dose escalation were allowed. Results: Sixteen pts (11M, 5 F) were enrolled on the study. The median age of the patients was 53 (21–84). Thirteen (81%) pts had R/R AML, and 3 (19%) had R/R ALL of which 5 (31%) had diploid and 6 (38%) had adverse cytogenetics. Median number of prior therapies was 3 (2–6). Pts enrolled at each dose level (mcg/m2) were: 6 (3 pts), 12 (5 pts), 24 (4 pts), 36 (4 pts). The median number of cycles delivered was 1 (0–5). The dose of 36 mcg/m2 was found to be above the MTD, with the DLT being grade 3 soft tissue edema. Other manifestations of vascular leak including grade I, II hypoalbuminemia, edema, and pleural effusions were seen in a number of patients starting at dose level 24 mcg/m2 and above. Other non-dose limiting toxicities included nausea, dyspnea, fatigue, bloating, and insomnia. One pt had a PR, 8 pts had stable disease, and 6 had progression. Pharmacokinetic characteristics in this population will be reported. Conclusions: SJG-136 is safe and active in patients with advanced leukemias. Edema and other vascular leak syndromes are characteristic toxicities of the agent at higher dose levels. 24 mcg/m2 is the recommended phase II dose for the daily x 5 schedule. No significant financial relationships to disclose.

Phase I/II study of a novel oral isotype-selective histone deacetylase (HDAC) inhibitor MGCD0103 in combination with azacitidine in patients (pts) with high-risk myelodysplastic syndrome (MDS) or acute myelogenous leukemia (AML)

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 7062-7062 ◽  
Author(s):  
G. Garcia-Manero ◽  
A. S. Yang ◽  
V. Klimek ◽  
S. Luger ◽  
W. M. Newsome ◽  
...  
Keyword(s):  
Phase I ◽  
Hdac Inhibitor ◽  
Dna Methyltransferase ◽  
Single Agent ◽  
Maximum Tolerated Dose ◽  
Myelogenous Leukemia ◽  
Clinical Activity ◽  
Relevant Dose ◽  
Aberrant Dna Methylation ◽  
Dose Levels

7062 Background: Aberrant DNA methylation and histone acetylation are common in leukemia. The HDAC inhibitor MGCD0103 (0103) and the DNA methyltransferase inhibitor azacitidine (aza); which is approved for all FAB subtypes of MDS, synergize preclinically and both have single-agent activity in MDS and AML. Based on these data, we developed a Phase I/II study of combination aza + 0103 in pts with AML and MDS. Phase I data is presented. Methods: Pts with advanced MDS (=10% marrow blasts), relapsed/refractory or untreated elderly patients with AML were treated with aza 75 mg/m2 SC daily for 7d of each 28-day cycle and 0103 110mg 3x/week starting on day 5. The primary endpoint was determination of the maximum tolerated dose (MTD) of the combination. The phase I portion followed “3+3” model; only 0103 was escalated. Results: Dose levels of 0103 explored were 35, 60, 90, 110 and 135 mg. 24 pts (those having received =1 dose of MGCD0103) have been evaluated; AML=22, MDS=2. Median age 67 (40–85), total cycles=56 (mean=2.3, range=1–11). Dose limiting toxicities observed: vomiting (1/8 pts at 90 mg), nausea & anorexia (2/3 pts at 135 mg), and anorexia (1/6 pts at 110 mg). The MTD of 0103 in the combination was determined to be110 mg. PK characteristics of neither drug was altered by co-administration. 7/9 pts had significant reduction of whole cell HDAC activity during treatment with the combination. Antileukemia activity was documented in 7 pts; 6 of which were among 14 at the 2 most relevant dose levels (90 & 110 mg): 3 CR, 1 PR, and 3 CR without platelet or neutrophil recovery (required for per- protocol response). Of these 7, 4 are ongoing and 3 have been discontinued: 1 to transplant and 2 for SAEs. Conclusions: The Phase I portion of the trial demonstrates that the 0103+aza combination is safe in pts with advanced AML/MDS, and has encouraging biologic & clinical activity. Phase II portion of the study is ongoing at MTD. Molecular studies are ongoing. No significant financial relationships to disclose.

A phase I trial of bexarotene, a retinoid X receptor agonist, in non-M3 acute myeloid leukemia

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 7061-7061
Author(s):  
D. E. Tsai ◽  
S. Luger ◽  
A. Kemner ◽  
C. Andreadis ◽  
A. Loren ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Phase I ◽  
Median Number ◽  
Clinical Activity ◽  
Cell Transplant ◽  
Platelet Counts ◽  
Cytotoxic Treatment ◽  
Dose Levels ◽  
Bone Marrow Blasts

7061 Background: In vitro, bexarotene inhibits the proliferation of non-M3 AML cell lines and induces differentiation of leukemic blasts. This phase I study was designed to evaluate the safety of escalating doses of bexarotene in patients with non-M3 AML and has completed enrollment. Methods: Bexarotene was administered daily until disease progression occurred. Dose escalation occurred in cohorts of 3–6 patients through 6 dose levels ranging from 100–400mg/m2. Results: 27 patients were enrolled: 19M/8F, median age 69 (range 51–82), 13 prior MDS, 12 primary refractory, median number of induction attempts 2, no prior chemotherapy 3, prior autologous stem cell transplant 5, 26 blood transfusion dependent, 18 platelet transfusion dependent, and 20 neutropenic. Despite prophylactic use of antihyperlipidemic agents, 4 patients developed grade ≥3 hypertriglyceridemia. Two patients developed a syndrome reminiscent of retinoic acid syndrome, consisting of dyspnea, pleural/pericardial effusions, and edema in the setting of a rising neutrophil count. This syndrome resolved with stopping bexarotene and initiating steroids. Evidence of activity was noted with bone marrow blasts decreasing to ≤5% in 4 patients. Seven patients showed evidence of neutrophil response (pretreatment median ANC 364/μL, range 28–1,242/μL, treatment ANC 3,540/μL, range 1,200–26,207/μL). Flow sorted peripheral blood neutrophils were collected from 3 of these patients and examined by FISH. Between 92–100% of neutrophils contained the patient's leukemic cytogenetic abnormality suggesting differentiation of the leukemic blasts. Eleven patients with platelet counts <100,000/μL had increases in their platelet counts >20,000/μL (peak range 40- 292x103/μL). Five of these patients with platelet counts <20,000/μL had improvement to 40–91,000/μL and became transfusion independent. Conclusions: Bexarotene is well tolerated at the dose levels studied. Evidence for clinical activity has been seen as exemplified by improvement in platelet counts, increased neutrophil counts and decreased bone marrow blasts. We postulate that bexarotene may induce leukemic blast differentiation in non-M3 AML and represent a novel non-cytotoxic treatment. No significant financial relationships to disclose.

A first-in-human phase I study of the oral p38 MAPK inhibitor LY2228820 dimesylate in patients with advanced cancer.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 3001-3001 ◽  
Author(s):  
Matthew P. Goetz ◽  
Anthony W. Tolcher ◽  
Paul Haluska ◽  
Kyriakos P. Papadopoulos ◽  
Charles Erlichman ◽  
...  
Keyword(s):  
Adverse Events ◽  
Phase I ◽  
P38 Mapk ◽  
Advanced Cancer ◽  
Phase I Study ◽  
Single Agent ◽  
Clinical Activity ◽  
Dependent Manner ◽  
Dose Levels ◽  
Dose Dependent

3001 Background: p38 MAPK regulates production of cytokines by the tumor microenvironment and its activation enables cancer cells to survive in the presence of oncogenic stress, radiation, chemotherapy, and targeted therapies. LY2228820 is a selective small-molecule inhibitor of p38 MAPK and preclinical studies demonstrate antitumor activity as a single agent and in combination with standard agents. We performed a phase I study to determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of LY2228820 and to characterize its pharmacokinetics and pharmacodynamics. Methods: Dose escalation was performed in a 3+3 design. LY2228820 was taken orally every 12 hours on days 1-14 of a 28-day cycle. Results: 54 patients received either capsules at 8 dose levels (10, 20, 40, 65, 90, 120, 160, and 200mg) or tablets at 5 dose levels (160, 200, 300, 420, and 560mg). For both formulations, Cmax and AUC increased in a dose-dependent manner. LY2228820 inhibited p38 MAPK induced phosphorylation of MAPKAP-K2 in peripheral blood with dose-dependent maximum inhibition from 10 to 70% across the dose range 10-200mg. The most common drug-related adverse events included fatigue, nausea, rash, constipation, vomiting, and pruritus. 1 patient (200mg) had DLT of erythema multiforme (Gr3) and 2 patients (560mg) had DLT of ataxia (Gr3) and dizziness (Gr2), respectively. Although the MTD was 420mg, the frequency of Gr1/2 adverse events (mainly rash, dizziness, and tremor) and observation of clinical activity at lower dose levels led to a recommended dose of 300mg (mean AUC0-24 = 11.7ug-hr/ml at steady state). Early clinical activity has been observed in ovary, breast, and kidney cancers. One patient with metastatic clear cell carcinoma of the kidney refractory to sorafenib, sunitinib, and temsirolimus had confirmed near partial response (29% decrease) after 8 cycles and remains on therapy. 15 patients (28%) achieved best overall response of stable disease, which in 12 patients (22%) was prolonged (≥4 cycles). Conclusions: LY2228820 demonstrates acceptable pharmacokinetics, safety, and early clinical activity as a single agent in advanced cancer. A phase II study for patients with ovary cancer is planned.

A Phase I, Multi-Center, Dose Escalation Study of Atiprimod in Patients with Refractory or Relapsed Multiple Myeloma (MM).

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 111-111 ◽  
Author(s):  
Michael Wang ◽  
Moshe Talpaz ◽  
Sundar Jagannath ◽  
Asher Alban Chanan-Khan ◽  
Raymond Alexanian ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Escalation ◽  
Treated Group ◽  
Median Number ◽  
Maximum Tolerated Dose ◽  
Clinical Activity ◽  
Dose Escalation Study ◽  
M Proteins ◽  
Dose Levels

Abstract Atiprimod (N-N-diethl-8, 8-dipropyl-2-azaspiro [4,5] decane-2-propanamine) is an orally bioavailable cationic amphilic compound that inhibited STAT 3 activation in MM cells. It effectively blocked the signaling pathway of interleukin-6, resulting in activation of caspase 3 and apoptosis (Amit-Vazina et al, Br J Cancer, 2005). Atiprimod has also induced cytotoxicity in dexamethasone, doxorubicin, and melphalan resistant MM cell lines (Hamasaki et al, Blood, 2005). Based on these encouraging in vitro data, we initiated a multi-center, phase I trial of atiprimod for patients (pts) with refractory or relapsed MM who had 2 prior lines of therapy and serum creatinine less than 2 mg/dl. Primary objectives were to evaluate the safety of atiprimod in MM pts and to identify the maximum tolerated dose (MTD). Each cycle of treatment consisted of 14 consecutive days of oral atiprimod followed by 14 consecutive days without treatment. A standard phase I dose escalation was used to determine MTD with atiprimod dose levels at 30 mg, 60 mg, 90 mg, 120 mg, and 180 mg. To date, 14 pts from 4 centers have been enrolled with evaluable data in 12 patients. Median age was 60 (range 44–64); median prior lines of therapy were 4 (range 3–7); median duration from initial treatment to registration to this trial was 36 months (range 19–76). Cohorts of 3 patients have been treated at 30, 60, 90,120 mg/day and 2 patients have been enrolled at the 180 mg/day level; no cohorts have been expanded because of dose-limiting toxicity. Median number of cycles received by MM pts was 2 (range 1–5). Common Grade 1 toxicity events included diarrhea, liver enzyme elevation and dyspepsia. There were two Grade 2 toxicity events with 1 neutropenia at the 90 mg/day level and 1 diarrhea at the 120 mg/day level. One pt had Grade 3 transaminase elevation (peak AST 402, ALT 469 units/L, bilirubin 0.5 mg/dl) during the second cycle that resolved on its own during the 14 day period off treatment. Two patients with rapidly rising serum M proteins prior to enrollment had a transient but clear reduction of their M proteins (30% and 80%) after the first 14 days of atiprimod. Two pts at higher dose levels noted subjective improvement in their bone pain. Atiprimod was generally well tolerated in this heavily treated group of MM pts. The MTD has not been reached. Although there has been no response to date, clinical activity is not expected until higher dose levels are evaluated (240 mg/day, 300 mg/day, and 360 mg/day). After the MTD has been established, the study of atiprimod combinations should be considered based on the in vitro assessment of synergy with other active agents.

Phase I study of TT-00420, a multiple kinase inhibitor, as a single agent in advanced solid tumors.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 3090-3090
Author(s):  
Sarina Anne Anne Piha-Paul ◽  
Binghe Xu ◽  
Filip Janku ◽  
Ecaterina Elena Dumbrava ◽  
Siqing Fu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Phase I ◽  
Disease Control ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Kinase Inhibitor ◽  
Single Agent ◽  
Cytokine Signaling ◽  
Concomitant Treatment ◽  
Dose Levels

3090 Background: TT-00420 is a spectrum-selective multi-kinase inhibitor that targets cell proliferation, angiogenesis, and immune-oncology pathways by inhibiting Aurora kinases A/B and Janus kinases (JAK) involved in cytokine signaling and receptor tyrosine kinases (FGFRs and VEGFRs) involved in the tumor microenvironment. TT-00420 has demonstrated anti-tumor activity in both in vitro and in vivo preclinical models of solid tumors, including triple-negative breast cancer (TNBC) and cholangiocarcinoma (CCA). Methods: The phase I, first-in-human dose escalation and expansion study of TT-00420 is enrolling adult patients with advanced or metastatic solid tumors. TT-00420 capsules in 1 mg or 5 mg formulation are administered orally once daily in 28-day cycles. Dose escalation is guided by Bayesian modeling with overdose control. The primary safety endpoints are to determine dose limiting toxicities (DLTs) and a dose recommended for dose expansion (DRDE). Secondary endpoints include pharmacokinetics (PK) and preliminary efficacy evaluated per RECIST v1.1 criteria. Results: As of February 17, 2021, 40 advanced solid tumor patients were enrolled in dose escalation cohorts and received at least one dose of TT-00420 in 7 dose levels: 1 mg q.d. (N=1), 3 mg q.d. (N=1), 5 mg q.d. (N=4), 8 mg q.d. (N=10), 10 mg q.d. (N=6), 12 mg q.d. (N=12), and 15 mg q.d. (N=6). DLTs were observed in 3 out of 32 DLT-evaluable patients, including 1 patient at 8 mg q.d. who had grade (Gr) 3 palmar-plantar erythrodysaesthesia syndrome and 2 patients at 15 mg q.d. who both had Gr 3 hypertension. Suspected adverse events (AEs) reported in ≥ 20% of patients across all tested dose levels include hypertension (any grade: n=17, 42.5%; Gr 3: n=8, 20.0%), diarrhea (n=10, 25.0%; Gr 3: n=1, 2.5%), vomiting (n=9, 22.5%; Gr 3: n=0), palmar-plantar erythrodysaesthesia syndrome (n=9, 22.5%; Gr 3: n=1, 2.5%), and nausea (n=8, 20.0%; Gr 3: n=1, 2.5%). No Gr 4 AEs, regardless of causality, were reported. Out of 26 patients who had at least one post-baseline scan, 4 (15.4%) had a best overall objective response of partial response (PR) and 13 (50.0%) had stable disease (SD). Of the patients who achieved PRs are 2 CCA patients (8 mg q.d., n=1; 10 mg q.d., n=1), 1 HER2-negative breast cancer patient (12 mg q.d.), and 1 TNBC (10 mg q.d.). Both CCA patients with PRs had disease control for ≥ 8 months. Of the patients who achieved SD, 1 salivary gland patient (5 mg q.d.) and 1 CCA patient (10 mg q.d.) had disease control for 8 months, and 2 TNBC patients (5 mg q.d., n=1; 8 mg q.d., n=1) had disease control for 6 months prior to disease progression. Conclusions: Toxicities observed in dose escalation cohorts were manageable with concomitant treatment and/or dose interruptions of TT-00420. 12 mg p.o. q.d. was recommended as the dose for dose expansion cohort for further safety and efficacy evaluation of TT-00420 capsules with focus on enrollment of TNBC and CCA patients. Clinical trial information: NCT03654547.

Clofarabine Combinations in Acute Myeloid Leukemia (AML) Salvage: A Dose-Finding Phase I Study of Clofarabine Plus Idarubicin and Clofarabine/Idarubicin Plus Cytarabine (ara-C).

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2803-2803
Author(s):  
Stefan Faderl ◽  
Alessandra Ferrajoli ◽  
William Wierda ◽  
Farhad Ravandi ◽  
Zeev Estrov ◽  
...  
Keyword(s):  
Phase I ◽  
Phase I Study ◽  
Single Agent ◽  
Response Rates ◽  
Maximum Tolerated Dose ◽  
Dose Finding ◽  
Unrelated Donor ◽  
Acute Leukemias ◽  
First Relapse ◽  
Dose Levels

Abstract Clofarabine is a second-generation nucleoside analog with single agent activity in acute leukemias. To try and improve efficacy, various combination trials are being conducted. In studies of clofarabine plus ara-C we reported overall response rates of 41% (CR 24%) in AML salvage and 60% (CR 52%) in untreated elderly AML with acceptable toxicity profile. To explore additional clofarabine combinations in AML we conducted a phase I study of clofarabine (C) with idarubicin (I) [CI] alone and with ara-C (A) [CIA] in pts with relapsed AML and high-grade MDS. Dose-limiting toxicities (DLT) were defined as ≥ grade 3 drug-related toxicities. Maximum tolerated dose (MTD) was determined by “3+3” method. Thirty-three patients (18 on CI and 15 on CIA) have been treated and are evaluable. Of 18 pts on CI, 6 were primary refractory and 12 in first relapse (median first remission duration [CRD1] 2 mos. [range 0–9]. Eleven pts had abnormal cytogenetics. Fourteen pts received prior ara-C-based regimens, 2 relapsed from allogeneic transplant (SCT). Median age: 57 yrs (range 24–71). Four dose levels have been explored. When C was given at 22.5mg/m2 i.v. daily x 5d and I at 12mg/m2 i.v. daily x 3d, 2 ≥ gr. 3 toxicities (diarrhea, rash, ↑ bili) occurred necessitating dose de-escalation. Subsequent levels included C at 15mg/m2 x 5d/I at 8mg/m2 x 3d (6 pts, 1 ≥ gr.3 toxicity [↑ bili]), C at 18 mg/m2 x 5d, I at 10mg/m2 x 3 d (3 pts, no DLT), and C at 22.5mg/m2 x 5d, I at 10mg/m2 x 3d (3 pts, no DLT). Three (17%) responses (2 CRp, 1 CR) occurred. Of 15 pts on CIA, 4 were primary refractory and 11 in first relapse. Median CRD1 was 9 mos (0–24). Eight pts had an abnormal karyotype. Seven pts received prior ara-C-based regimens and 2 failed unrelated donor SCT. Median age: 58 yrs (23–78). Three dose levels were evaluated. At 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, 2 of 3 pts developed ≥ gr.3 toxicities (↑ bili, diarrhea) necessitating dose de-escalation. Subsequent levels included C at 15mg/m2 x 5d, I at 6mg/m2 x 3d, A at 0.75g/m2 x 5d (6 pts, 1 with ≥ gr. 3 rash, ↑ bili), and C at 22.5mg/m2 x 5d, I at 6mg/m2 x 3d, and A at 0.75g/m2 x 5d (6 pts, 1 with ≥ gr. 3 ↑ bili). Nine (60%) responses (8 CR, 1 CRp) occurred. Further dose escalation of clofarabine is planned in both trials. The preliminary results indicate feasibility of the combinations. The higher response rates with CIA need to be evaluated in view of different pt. characteristics between the two trials.

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