A phase I study of chronically dosed, single-agent veliparib (ABT-888) in patients (pts) with either BRCA 1/2-mutated cancer (BRCA+), platinum-refractory ovarian cancer, or basal-like breast cancer (BRCA-wt).

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 3054-3054 ◽  
Author(s):  
Shannon Leigh Huggins-Puhalla ◽  
Jan Hendrik Beumer ◽  
Leonard Joseph Appleman ◽  
Hussein Abdul-Hassan Tawbi ◽  
Ronald G. Stoller ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Ovarian Cancer ◽  
Phase I ◽  
Dose Escalation ◽  
Methylation Status ◽  
Single Agent ◽  
Parp Inhibition ◽  
Low Grade ◽  
Basal Like Breast Cancer ◽  
Dose Levels

3054 Background: Veliparib (ABT-888) is an oral, potent inhibitor of PARP 1/2. Preclinically, PARP inhibitors have activity in tumors with defective homologous recombination (HR), particularly those that are BRCA+. Reduced levels of BRCA expression have been observed in ovarian cancer and basal-like breast cancer, which share genotypic and phenotypic similarities with BRCA+ cancers. We postulated that these tumors types may be similarly sensitive to single-agent PARP inhibition. This study sought to establish the maximum tolerated dose (MTD), dose limiting toxicities (DLT), pharmacokinetic and pharmocodynamic properties, and preliminary efficacy of chronically-dosed veliparib. Methods: A 3+3 dose escalation phase I trial was performed. Nine dose levels (DL) were planned, and dose escalation started at 50 mg BID to a maximum of 500 mg BID. Veliparib was administered orally continuously on a 28 day cycle. Results: 63 pts have been enrolled to date. Thirty-eight were BRCA+ (20 ovary, 12 breast, 2 pancreas, and one each - prostate, peritoneal, fallopian tube, endometrial); 25 BRCA-wt. (21 breast, 4 ovarian). DLTs occurred at the following dose levels: BRCA+: gr. 2 thrombocytopenia at 50 mg BID; BRCA+: gr.3 Nausea/vomiting at 400 mg BID; BRCA-wt: gr 2 seizure at 400 mg BID. The MTD has not been determined and 500 mg BID is presently enrolling. Notable toxicities have included low-grade fatigue and nausea. PK was linear and non-saturable with t ½ of 5 h. The number of cycles administered ranged from 1- 15, median 2. In BRCA+ pts, there were 2 partial responses (breast, ovarian) and 10 pts had evidence of prolonged SD ≥ 4 months. In BRCA-wt pts, there was 1 PR (breast) and 7 pts with SD≥ 4 months. Correlative studies, including assessment of PAR inhibition and BRCA methylation status, are ongoing. Conclusions: Veliparib is tolerable on a continuous oral dosing schedule with evidence of anti-tumor activity seen in BRCA+ and BRCA-wt tumors. A mandatory biopsy expansion cohort is planned at the recommended phase II dose, which will allow further insights regarding efficacy and mechanisms of resistance to PARP inhibition.

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.

Outcome of BRCA 1/2-mutated (BRCA+) and triple-negative, BRCA wild type (BRCA-wt) breast cancer patients in a phase I study of single-agent veliparib (V).

2014 ◽  
Vol 32 (26_suppl) ◽  
pp. 135-135 ◽  
Author(s):  
Shalu Pahuja ◽  
Jan Hendrik Beumer ◽  
Leonard Joseph Appleman ◽  
Hussein Abdul-Hassan Tawbi ◽  
Ronald G. Stoller ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Ovarian Cancer ◽  
Phase I ◽  
Dose Escalation ◽  
Triple Negative ◽  
Single Agent ◽  
Parp Inhibitors ◽  
Maximum Tolerated Dose ◽  
Serous Ovarian Cancer ◽  
Number Of Patients

135 Background: Veliparib (V) (ABT-888) is an oral, potent inhibitor of PARP 1/2. PARP inhibitors have preclinical and clinical efficacy in BRCA+ malignancies. There are genotypic and phenotypic similarities between BRCA+ cancers, serous ovarian cancer and basal-like breast cancer and we postulated that these tumors types may be similarly sensitive to single-agent PARP inhibition. This study sought to establish the maximum tolerated dose (MTD), dose -limiting toxicities (DLT), pharmacokinetic and pharmocodynamic properties, and preliminary efficacy of chronically-dosed V in 2 cohorts of patients, BRCA+ and BRCA-wt (consisting of serous ovarian cancer and triple-negative breast cancer (TNBC). Methods: A 3+3 dose escalation phase I trial was performed. Nine dose levels (DL) were planned, and dose escalation started at 50 mg BID to a maximum of 500 mg BID to determine a maximum tolerated dose (MTD) and recommended phase II dose (RP2D). V was administered orally continuously on a 28 day cycle. BRCA+ and BRCA-wt patients were enrolled in 2 separate cohorts with 2 separate escalations. Results: 98 (70 BRCA+ and 28 BRCA-wt) pts have been enrolled. The maximum administered dose (MAD) was 500mg BID and the MTD/RP2D is 400mg BID for both cohorts. 59 BRCA+ pts and 24 BRCA-wt pts (21 TNBC and 3 ovary) were evaluable for response. ORR was defined as CR+PR and clinical benefit rate (CBR) as CR+PR+SD > 6 months. Results are summarized in the table. Conclusions: There is evidence of anti-tumor activity with V comparable to that of other PARP inhibitors in the BRCA+ population. There was indication of dose responsiveness with greater activity in this population at higher doses. There is less activity in the mostly TNBC, BRCA-wt population, although there was evidence of benefit in a small number of patients. Ongoing tissue correlative studies will help to identify potential mechanisms of sensitivity and resistance. Clinical trial information: NCT00892736. [Table: see text]

A phase I dose escalation trial of a daily oral CDK 4/6 inhibitor PD-0332991

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 3550-3550 ◽  
Author(s):  
P. J. O’Dwyer ◽  
P. LoRusso ◽  
A. DeMichele ◽  
V. Gupta ◽  
A. Barbi ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Escalation ◽  
Stable Disease ◽  
Single Agent ◽  
Study Results ◽  
Alternative Schedule ◽  
Effect Of Food ◽  
Tumor Types ◽  
Dose Levels ◽  
Cancer Côlon

3550 Background: PD-0332991 is a novel oral inhibitor of CDK 4/6, which is active against Rb positive tumors and has never before been tested in humans. A phase I dose escalation trial of PD-0332991 administered as a daily oral single agent was conducted to investigate safety, pharmacokinetics and pharmacodynamics in patients with advanced cancer. Methods: PD-0332991 was administered daily for 21 days in 28-day cycles (Schedule 3/1) to patients in successive dose escalating cohorts at doses from 25 mg to 150 mg QD. An alternative schedule of 14 days dosing in 21-day cycles (Schedule 2/1) was tested at 100 mg to 225 mg QD. Patients with advanced Rb positive solid tumors were enrolled in the study. Results: Fifty-seven patients have been enrolled into the study. The most common tumor types were: breast, colorectal, liposarcoma, and melanoma. The median age across the study was 57 years. For Schedule 3/1, the MTD/RP2D was determined to be 125 mg QD. For Schedule 2/1, the MTD/RP2D is still to be identified but the maximum administered dose (MAD) was determined to be 225 mg QD. Six DLTs have been observed, all relating to myelosuppression. The most common AEs were neutropenia, anemia, fatigue, nausea, constipation, vomiting and diarrhea. Concentrations were moderately variable (% CV range in AUC on Day 8 of Cycle 1 was 14–64%) with dose-dependent increases in exposure observed following PD-0332991 administration (mean AUC(0–10 hr) values were 724 and 1,500 ng.hr/mL at the 125 mg and 225 mg dose levels, respectively). The effect of food on PD-0332991 pharmacokinetics is currently being evaluated. In Schedule 3/1, there have been 6 patients with stable disease (= 10 cycles) with 3 patients (one each with breast cancer, colon cancer and ovarian cancer) with stable disease for at least 20 cycles. In Schedule 2/1, one patient has had stable disease for at least 10 cycles. Updated data will be presented. Conclusions: The principal and dose limiting toxicity of PD- 0332991 is myelosuppression. The RP2D for Schedule 3/1 is 125 mg QD. The MAD has been determined for Schedule 2/1 as 225 mg QD and the dose in this schedule has been de-escalated to 200 mg QD to evaluate the MTD. Tumor specimens, when available, from patients in both schedules are also being tested for pharmacodynamic modulation of phospho-RB protein. No significant financial relationships to disclose.

Phase I experience with first in class TnMUC1 targeted chimeric antigen receptor T-cells in patients with advanced TnMUC1 positive solid tumors.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e14513-e14513
Author(s):  
Rodolfo Gutierrez ◽  
Payal D Shah ◽  
Omid Hamid ◽  
Alfred L. Garfall ◽  
Avery Posey ◽  
...  
Keyword(s):  
T Cells ◽  
Phase I ◽  
Solid Tumors ◽  
Chimeric Antigen Receptor ◽  
Dose Escalation ◽  
Intracellular Signaling ◽  
Antigen Receptor ◽  
Low Grade ◽  
Gi Symptoms ◽  
Dose Levels

e14513 Background: MUC1 is a glycoprotein that is expressed in healthy tissues on the luminal surface of simple and glandular epithelium. In tumors that arise from these cells, an alternate form with aberrant glycosylation is frequently over expressed and distinguishes tumor associated TnMUC1 from normal MUC1. We have generated a novel chimeric antigen receptor (CAR) targeting the TnMUC antigen comprised of a mouse anti-human scFv derived from the monoclonal antibody 5E5 which recognizes the epitope comprising Tn glycan of MUC1, a CD8a transmembrane region and dual CD2 and CD3z intracellular signaling domains. CD2 signaling in T-cells has been demonstrated to result in delayed exhaustion. The novel incorporation of this co-stimulatory domain may lead to enhanced persistence of the CART cells which is believed to be critical for efficacy in solid-tumors. Methods: This is a multi-center first in human Phase I study to evaluate the safety and preliminary efficacy of CART-TnMUC1-Cells for the treatment of solid-tumors. Solid-tumors included in the dose-escalation phase include metastatic treatment-resistant ovarian cancer (OC), pancreatic adenocarcinoma (PC), triple-negative breast cancer (TNBC) or non-small lung cancer (NSCLC). All patients must have TnMUC1 expression as determined by immunohistochemistry. Results: As of January 2021, a total of six patients were treated. Three in Cohort 1 (no lymphodepletion; dose = 1-2 x 107 TDN CART cells; tumors = 1 OC, 1 TNBC and 1 PC) and 3 in Cohort 2 (flu/cy lymphodepletion; dose = 1-2 x 107 TDN CART cells; tumors = 1 NSCLC and 2 OC). None of the patients treated experienced DLT’s. The trial is currently enrolling to Cohort 3 (flu/cy lymphodepletion, 5-6 x 107 TDN). No CRS, neurotoxicity, serious adverse reactions and no on-target/off-tumor toxicity was observed at these dose levels. The most common AE’s were low-grade GI symptoms (e.g., nausea, abdominal pain) in 5/6 patients (83.3%), generalized disorders (e.g., chills, fatigue) in 5/6 (83.3%) and hematologic disorders (e.g., anemia, neutropenia) in 3/6 (50%) of patients. CAR expansion was demonstrated in all patients and was improved in Cohort 2 following LD chemotherapy. Preliminary efficacy assessed by RECIST v1.1 at Day +28 demonstrate SD in all patients in Cohort 2. Conclusions: This is the first report of a novel CART-TnMUC1 construct containing a CD2 co-stimulatory domain that has been used in clinical trials for the treatment of refractory solid-tumor malignancies. While the study is still early in dose-escalation having completed only 2 of 6 planned dose levels there is no evidence of safety concerns or on-target/off-tumor toxicity. Additional safety, efficacy and biomarker data is currently being reviewed and will be presented. Clinical trial information: NCT04025216.

A phase I/IB dose-escalation study of BEZ235 in combination with trastuzumab in patients with PI3-kinase or PTEN altered HER2+ metastatic breast cancer.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 508-508 ◽  
Author(s):  
Ian E. Krop ◽  
Cristina Saura ◽  
Jordi Rodon Ahnert ◽  
Carlos Becerra ◽  
Carolyn D. Britten ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Phase I ◽  
Dose Escalation ◽  
Single Agent ◽  
Metastatic Breast ◽  
Pi3k Pathway ◽  
Dose Escalation Study ◽  
Her2 Breast Cancer ◽  
Disease Stabilization

508 Background: Alterations in the PI3K/AKT/mTOR pathway have been implicated in resistance to trastuzumab (T) in HER2+ breast cancer. BEZ235, a potent oral dual PI3K/mTORC1/2 inhibitor, has demonstrated growth inhibition and apoptosis in HER2+ breast cancer models, including those harboring PI3K pathway alterations, and with T resistance. In a Phase I study, BEZ235 was well tolerated as a single agent in pts with advanced solid tumors. The aim of this study was to determine the MTD of BEZ235 in combination with T in pts with T-resistant HER2+ metastatic breast cancer (mBC) with alterations of the PI3K pathway. Methods: Pts with T-resistant HER2+ mBC (i.e. disease progression during adjuvant therapy or metastatic disease on therapy with T) received oral BEZ235 daily, with weekly T (2 mg/kg). Pts were eligible for enrollment if a tumor sample was demonstrated to contain a molecular alteration of PIK3CA and/or PTEN. Dose escalation was guided by a Bayesian logistic regression model with overdose control. Results: As of 23 Sep 2011, 15 of the 19 enrolled pts were evaluable for dose escalation analysis. BEZ235 was evaluated at 3 dose levels: (1) 400 mg/day (3 pts); (2) 600 mg/day (6 pts); (3) 800 mg/day (10 pts), administered either in capsule form (400 mg) or in sachet form (600 mg and 800 mg). The MTD of BEZ235 in combination with T was estimated to be 600 mg/day. Observed DLTs were G3 nausea at 600 mg/day (1 pt), and G3 nausea, G3 fatigue and G3 skin rash (1 pt each) at 800 mg/day. The most frequent G3/4 adverse events (CTCAE v3.0) suspected to be related to study treatment were diarrhea (4 pts) and nausea (2 pts). No deaths related to study treatment occurred. 1 pt with lung and brain metastases had a partial response. 4 pts had disease stabilization for ≥4 cycles (16 weeks), including 1 pt with liver metastases, in whom BEZ235/T treatment resulted in disease stabilization for more than 21 cycles (84 weeks). Conclusions: BEZ235in combination with T demonstrated an acceptable safety profile in pts with HER2+ mBC and PI3K pathway alterations. Following the Bayesian model recommendation, the MTD for BEZ235 in combination with T was estimated to be 600 mg/day. The safety expansion arm is ongoing at the MTD.

Mirvetuximab soravtansine (IMGN853), a folate receptor alpha (FRα)-targeting antibody-drug conjugate (ADC), in platinum-resistant epithelial ovarian cancer (EOC) patients (pts): Activity and safety analyses in phase I pooled expansion cohorts.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 5547-5547 ◽  
Author(s):  
Kathleen N. Moore ◽  
Ursula A. Matulonis ◽  
David M. O'Malley ◽  
Jason A. Konner ◽  
Lainie P. Martin ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Phase I ◽  
Folate Receptor ◽  
Single Agent ◽  
Phase Iii ◽  
Platinum Resistance ◽  
Low Grade ◽  
Antibody Drug Conjugate ◽  
Pivotal Phase ◽  
Platinum Resistant

5547 Background: The early clinical evaluation of mirvetuximab soravtansine (IMGN853), an ADC that comprises a FRα-binding antibody linked to the tubulin-disrupting maytansinoid DM4, has revealed encouraging signs of activity in pts with ovarian cancer. A pooled analysis of safety and efficacy was performed including individuals with platinum-resistant EOC, enrolled across three expansion cohorts of an ongoing phase I trial (NCT01609556), who met the eligibility criteria for the pivotal phase III study of IMGN853 (FORWARD I; NCT02631876). Methods: Pts were administered IMGN853 intravenously once every 3 weeks at 6 mg/kg using adjusted ideal body weight dosing. Responses were assessed according to RECIST 1.1 and adverse events (AEs) evaluated by CTCAE v4.0. Results: A total of 37 EOC pts treated as part of the three phase I expansion cohorts (pooled population; n = 113) met the FORWARD I enrollment criteria of moderate to high tumor FRα levels (≥ 50% of cells with ≥ 2+ FRα expression) and 1-3 prior lines of therapy. In this group of pts with platinum-resistant disease, confirmed objective tumor responses were observed in 17 individuals (1 complete response [CR] and 16 partial responses [PR]) for an overall response rate (ORR) of 46% (95% CI, 29.5, 63.1) and a median PFS of 6.7 months (95% CI, 4.1, 9.0). The safety profile of the pooled population was consistent with that previously reported (ASCO Annual Meeting, 2016) with the most common AEs being diarrhea, fatigue, nausea, and blurred vision; these were low grade and readily managed. Conclusions: IMGN853 continues to be characterized by favorable tolerability and encouraging activity in pts with platinum-resistant EOC. In particular, both the ORR (46%) and PFS (6.7 months) achieved in this group of pts are superior to outcomes typically seen with established single-agent chemotherapy within the setting of primary platinum resistance. Overall, these analyses provide continued, robust support for the patient eligibility strategy employed in the phase III evaluation of IMGN853. Clinical trial information: NCT01609556.

First-in-human phase I/Ib multicenter, open-label dose escalation study to assess safety and tolerability of PMD-026 in patients with metastatic breast cancer with expansion in metastatic triple negative breast cancer.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. TPS1110-TPS1110
Author(s):  
Muralidhar Beeram ◽  
Judy Sing-Zan Wang ◽  
Lida A. Mina ◽  
Amita Patnaik ◽  
Mary Rose Pambid ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Drug Resistance ◽  
Metastatic Breast Cancer ◽  
Phase I ◽  
Triple Negative Breast Cancer ◽  
Dose Escalation ◽  
Triple Negative ◽  
Single Agent ◽  
Metastatic Breast ◽  
Open Label

TPS1110 Background: Metastatic triple negative breast cancer (mTNBC) has a poor prognosis with limited durable treatment options. RSK (P90 ribosomal S6 kinase) is a signaling protein at the convergence point of PDK-1 and MAPK signaling pathways. RSK1-3 phosphorylates transcription factors, including Y-box binding protein-1 (YB-1), thereby inducing drug resistance and cancer growth genes. Phosphorylated YB-1 is involved in tumor cell survival, proliferation, and drug resistance. In human breast tumor samples, RSK2 protein is expressed across all breast cancer subtypes (TNBC, ER+ and HER2+) and is associated with poor overall survival. Expression of RSK2 is found in approximately 87% of mTNBC tumors and of those tumors approximately 41% have very high expression of RSK2. PMD-026 is a potent, oral, small molecule RSK inhibitor with high selectivity for RSK2. Preclinical in vivo studies have demonstrated activity both as a single agent and in combination with standard of care therapies. Further, a CAP/CLIA certified IHC method has been developed with Roche to determine tumor expression of RSK2. Methods: This single-arm, open-label, first-in-human, phase I/Ib study evaluates the safety and efficacy of single agent PMD-026 in patients with metastatic breast cancer for whom standard therapies are no longer effective. During dose escalation, the study utilizes an accelerated titration design with single patient cohorts until the occurrence of DLT or Grade 2+ toxicity; then reverts to 3+3 design to define the maximally tolerated dose (MTD) and recommended phase II dose (RP2D). The dose expansion portion will enroll approximately 20 patients with mTNBC. Patients are dosed orally once daily in 21-day cycles with measures to adapt the dosing schedule based on the pharmacokinetic (PK) data, as needed. Tumor tissue is required for all enrolled patients; RSK2 expression will be retrospectively correlated with clinical outcomes. The primary objectives are to determine safety and tolerability of PMD-026, determine the MTD, define a RP2D, and assess anti-tumor activity of PMD-026 in patients with TNBC. Secondary objectives are to evaluate PK, time to response, mTNBC subtyping using NanoString, and duration of response of PMD-026. To date, cohorts 1 and 2 have been completed without DLT. Enrollment to cohort 3 began in January 2020. Clinical trial information: NCT04115306 .

A Phase I Dose-Escalation Trial of Oral Clofarabine for Relapsed/Refractory Non-Hodgkin Lymphoma

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1775-1775
Author(s):  
Jeremy S Abramson ◽  
Tak Takvorian ◽  
Eric D Jacobsen ◽  
Jennifer R Brown ◽  
Jeffrey A. Barnes ◽  
...  
Keyword(s):  
Phase I ◽  
B Cell ◽  
Dose Level ◽  
Dose Escalation ◽  
Median Number ◽  
Hematologic Toxicity ◽  
Low Grade ◽  
Non Hodgkin Lymphoma ◽  
Grade 3 ◽  
Dose Levels

Abstract Abstract 1775 Background: Clofarabine is a second-generation purine analogue currently FDA-approved for intravenous use for relapsed/refractory pediatric ALL. Purine analogues demonstrate significant clinical activity in non-Hodgkin lymphomas (NHL), though clofarabine offers potential pharmacologic advantages over existing agents. Clofarabine is a more efficient substrate for deoxycytidine kinase, more completely inhibits ribonucleotide reductase and DNA polymerase α, and demonstrates improved activity in cells that are non-dividing or have a low proliferation rate. This phase I trial is the first evaluation of an oral formulation of clofarabine in relapsed or refractory non-Hodgkin lymphoma. Patients and Methods: The primary objective was to determine the maximum tolerated dose (MTD) and define dose-limiting toxicities (DLT). Efficacy was a secondary objective. Patients (pts) were eligible if they had relapsed or refractory B-cell or T-cell NHL without prior stem cell transplant. All pts were required to have adequate organ function and performance status ≤2 as well as absence of both CNS involvement and HIV infection. No routine infectious prophylaxis was given. Patients were treated at 4 dose levels (1mg, 2mg, 4mg and ultimately 3mg) with oral clofarabine administered once daily on days 1–21 of a 28 day cycle for up to 6 cycles. Three to 6 pts were treated at each dose level in a traditional 3+3 design. Response assessment occurred after cycles 2 and 6. DLT was assessed during cycle 1 and was defined as Grade 4 neutropenia or thrombocytopenia occurring for ≥5 days, any grade 3–4 non-hematologic toxicity, and grade 2 non-hematologic toxicity that did not recover prior to the subsequent cycle of therapy. Results: Twenty-one pts were enrolled on the dose-escalation phase of the study. The median age was 63 years (range 51–85). The median number of prior regimens was 2 (range 1–7). Histologies included follicular lymphomas (FL; 5 pts), small lymphocytic lymphomas (SLL; 5 pts), diffuse large B-cell lymphomas (DLBCL; 4 pts), marginal zone lymphomas (MZL; 4 pts), mantle cell lymphomas (MCL. 2 pts) and lymphoplasmacytic lymphoma (LPL; 1 pt). Median number of cycles administered was 5.5. No DLTs were observed at the 1mg or 2mg dose levels. Three pts were accrued at 4mg with 1 patient experiencing DLT of persistent grade 3 thrombocytopenia and grade 4 neutropenia. No additional DLTs occurred in the cohort, but the majority of pts required late dose reductions due to grade 3–4 hematologic toxicity. The dose was therefore de-escalated to 3mg and 6 additional pts were accrued. No DLTs were observed at the 3mg dose level with a median of 6 cycles administered (range 5–6); 3mg was declared the recommended phase 2 dose. Grade 3–4 hematologic toxicity included neutropenia (7 pts), thrombocytopenia (4 pts), and anemia (2 pts). Grade 1–2 non-hematologic toxicities were uncommon, and included fatigue, diarrhea, cough, and dizziness. There were no grade 3–4 non-hematologic toxicities. Seventeen pts completed one cycle of therapy and were evaluable for response. Radiographic disease reduction was observed in 11 of 17 pts (65%). The overall response rate (ORR) was 35% (6 of 17), all partial responses (PR). Responders included FL (2 pts), MZL (2 pts), SLL and LPL (1 pt ea.). ORR among low grade histologies (FL, MZL, SLL) was 43% in this phase 1 trial. Seven pts had stable disease, including 5 pts with reduction in tumor size that did not reach threshold for PR. Of the 4 pts with progressive disease, 2 had DLBCL, 1 had MCL and 1 had FL with biopsy following relapse identifying ALK-negative anaplastic large T-cell lymphoma. Of the 4 pts not evaluable for response, 1 pt died of progressive DLBCL during cycle 1 on dose level 1 and was replaced, 1 pt was the DLT pt on the 4mg dose level and was removed due to prolonged cytopenias, and 2 pts withdrew consent (1pt at 4mg, 1pt at 3mg), and were replaced. The 3mg dose level has been expanded in a 10-patient dose-expansion cohort limited to low-grade NHL and MCL. Conclusions: Oral clofarabine demonstrates encouraging tolerability and efficacy in relapsed B-cell NHL, particularly in low-grade histologies, warranting further investigation. Disclosures: Abramson: Genzyme: Consultancy. Off Label Use: Clofarabine is not FDA approved for NHL.

First-in-human phase I study of CetuGEX, a novel anti-EGFR monoclonal antibody (mAb) with optimized glycosylation and antibody dependent cellular cytotoxicity.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 3008-3008
Author(s):  
Walter Fiedler ◽  
Cristiana Sessa ◽  
Luca Gianni ◽  
Sara Cresta ◽  
Henning Schulze-Bergkamen ◽  
...  
Keyword(s):  
Phase I ◽  
Single Agent ◽  
Growth Factor Receptor ◽  
Complete Response ◽  
Low Grade ◽  
Full Potential ◽  
Immunological Parameters ◽  
Flat Dose ◽  
Almost All ◽  
Dose Levels

3008 Background: Epidermal growth factor receptor (EGFR) is a validated target in cancer. EGFR antagonists in clinical use do not exploit the full potential of this target. CetuGEX is an IgG1 mAb against EGFR. Fully human and optimized glycosylation lead to a 10- to 250-fold improvement of ADCC-mediated tumor cell killing in all FcγRIIIa allotypes and lack of immunogenic carbohydrate-chains, compared to cetuximab. Methods: Eligible patients with advanced solid tumors, progressing after standard treatment, were enrolled into this phase I, first-in-human, multicenter, single agent dose escalation trial. PK, PD and immunological parameters were assessed. Endpoints were safety and tolerability and secondarily pharmacokinetics, immunogenicity and anti-tumor activity. Results: 41 patients were treated on a q1w (8 dose levels from 12 to 1,370 mg flat dose), or q2w (990 mg flat) schedule. 25 pts had received at least 8 weekly doses (per protocol population [PP]).The most frequently observed drug-related AE were nausea (20%), vomiting (20%), hypertension (20%), almost all low grade and acneiform dermatitis (25%), only grade 1 or 2. Infusion-related reactions (IRR), virtually restricted to the first infusion, were associated with cytokine secretion: IL-6, IL-8, TNFα, IFNγ and IP-10 as marker of macrophage activation. Optimization of infusion scheme and premedication reduced IRRs in severity and frequency from 76% to 57% mainly of low grade. Blood NK cells were reduced as sign of redistribution. Activity was seen over all dose levels. One patient with NSCLC achieved a complete response. One patient with metastatic colorectal cancer had a partial response, another 2 patients with esophageal and gastric cancer without measurable disease at study entry had marked improvement of symptoms and normalization of tumor markers. Additional 15 pts had stable disease lasting from 8 weeks to over a year, including several minor responses, leading to a clinical benefit rate of 46% (19/41) in the overall and 76% (19/25) in the PP population. PK supports q1w and q2w dosing. Conclusions: CetuGEX shows clear signs of activity and acceptable toxicity. Phase II will soon be initiated. Clinical trial information: NCT01222637.

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