CTNI-36. SAFETY OF ONC201 ADMINISTERED TWO CONSECUTIVE DAYS PER WEEK IN PEDIATRIC H3 K27M-MUTANT GLIOMA PATIENTS

Abstract ONC201, an anti-cancer DRD2 antagonist and ClpP agonist, is in Phase II trials for adult H3 K27M-mutant diffuse midline gliomas. The recommended phase 2 dose (RP2D) of 625mg ONC201 once a week has been established as a biologically active dose that is well tolerated in adult and pediatric populations. Radiographic regressions with single agent ONC201 have been reported in recurrent H3 K27M-mutant glioma patients. In another study, twice/week dosing was explored in adult patients and deemed to be safe (no DLTs observed). This warranted exploration of twice/week dosing in pediatric patients and will be discussed in this presentation. This multi-arm, dose-escalation and dose-expansion trial (ONC014; NCT03416530) determined the pediatric RP2D of ONC201 administered once per week and twice per week on two consecutive days. ONC201 was orally administered and scaled by body weight. Dose escalation was performed by a 3 + 3 design beginning with two 125mg capsules less than the adult RP2D equivalent. Twelve children (8 females; 4 males) with H3 K27M-mutant gliomas (pons: 8; thalamus: 2; spinal cord: 2) aged 4-19 years have been treated post-radiation: 3 at dose level -1; 3 at dose level 1; 6 as part of the dose expansion cohort on dose level 2. Median KPS was 90 (range 70-100). One treatment cycle was 21 days (6 doses), which also defined the DLT window. Patients were on-treatment for a median length of 4 cycles (range: 2-11). Twice weekly dosing of ONC201 was tolerated well, as observed with weekly dosing, with no instance of DLT. A total of 4 SAEs were reported, none of which were related to the study drug. The most common AEs (regardless of relatedness) included headache, facial nerve disorder, abducens nerve disorder, nausea, fatigue and ataxia. Additional safety data, PK, and clinical outcomes from this arm will be reported.

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Phase I study of mesothelin-targeted immunotoxin LMB-100 in combination with tofacitinib in patients with advanced pancreatobiliary cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.3051 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 3051-3051

Author(s):

Nebojsa Skorupan ◽

Mehwish Iqra Ahmad ◽

Guillaume Joe Pegna ◽

Cody J. Peer ◽

Jane B. Trepel ◽

...

Keyword(s):

Solid Tumors ◽

Dose Level ◽

Dose Escalation ◽

Single Agent ◽

Primary Objective ◽

Pseudomonas Exotoxin A ◽

Recombinant Immunotoxin ◽

Level 1 ◽

Expansion Cohort ◽

Almost All

3051 Background: LMB-100 recombinant immunotoxin consists of a mesothelin-binding Fab for targeting a modified Pseudomonas exotoxin A payload to tumors. Previous clinical trials demonstrated that almost all patients formed anti-drug-antibodies (ADAs) to LMB-100 that made administration beyond cycle 2 ineffective. Tofacitinib is an oral JAK inhibitor that prevented formation of ADAs against a closely related immunotoxin in pre-clinical studies. The primary objective of the dose escalation cohort was assessment of safety and tolerability of LMB-100 given with tofacitinib to patients with mesothelin-expressing solid tumors. The primary objective of the expansion cohort was to determine whether co-administration of tofacitinib delays formation of neutralizing LMB-100 ADAs. Methods: Patients (n = 13) with pancreatic adenocarcinoma and other mesothelin-expressing solid tumors (n = 3; cholangiocarcinoma, appendix, cystadenocarcinoma) were treated for up to 3 cycles with LMB-100 as a 30-minute infusion on days 4, 6, and 8 at two dose levels (100 and 140 mcg/kg) and co-treated with oral tofacitinib for the first 10 days of the cycle (10 mg BID). Results: Dose level 1 of LMB-100 was started at 100 mcg/kg one dose level below the single agent MTD. Dose escalation to 140 mcg/kg (dose level 2) resulted in DLTs in 2 of the 3 patients treated: grade 3 cardiac toxicity and grade 4 hyponatremia, both attributed to capillary leak syndrome. Ultimately, 7 patients were treated at dose level 1 without DLTs and 100 mcg/kg was chosen as the LMB-100 dose for the expansion cohort. The last of 6 patients treated in the expansion cohort developed grade 4 pericardial effusion leading to early closure of the study for toxicity. No objective responses were seen. Of the 8 patients who received two cycles of treatment at MTD, 4 met prespecified criteria for ADA prevention, and 2 patients who went on to receive cycle 3 had detectable LMB-100 plasma drug levels after administration. Conclusions: LMB-100 was unable to be co-administered safely with tofacitinib. ADA formation was prevented in 2 patients through 3 cycles, a rare occurrence. Clinical trial information: NCT04034238.

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A phase I trial of the oral hedgehog inhibitor taladegib (LY2940680) in combination with weekly paclitaxel in patients with advanced, solid tumours.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.2594 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. 2594-2594

Author(s):

Rosalind Margaret Glasspool ◽

Sarah Patricia Blagden ◽

Michelle Lockley ◽

James Paul ◽

Carol Hopkins ◽

...

Keyword(s):

Phase I ◽

Dose Level ◽

Dose Escalation ◽

Single Agent ◽

Primary Objective ◽

Solid Tumours ◽

Muscle Cramp ◽

Weekly Paclitaxel ◽

Level 1 ◽

Level 2

2594 Background: Aberrant Hedgehog (Hh) signaling is implicated in carcinogenesis and is associated with poor prognosis in multiple tumours types. Hh inhibitors increase sensitivity to paclitaxel in taxane-resistant cell lines. Taladegib is an orally bioavailable, potent inhibitor of Smoothened, a key Hh pathway component, with activity in basal cell carcinoma. The single agent recommended dose is 400mg od. We present the dose escalation phase of a phase I study of weekly paclitaxel with oral taladegib. Methods: Primary objective: determine the dose limiting toxicity (DLT) and maximum tolerated dose (MTD) of taladegib on a continuous oral daily dosing regimen in combination with paclitaxel (80mg/m2, iv, day 1, 8 and 15 q 28) in patients with advanced solid cancers. Secondary objectives: assess the safety and tolerability, determine the recommended phase II dose (RP2D), and evaluate the pharmacokinetics of taladegib and paclitaxel. Exploratory objective: assess preliminary efficacy. A standard 3 + 3 dose escalation design was used. All patients received up to 6 cycles of paclitaxel. In addition, successive cohorts received continuous oral taladegib continued until progression or unacceptable toxicity as follows: dose level 1: 100mg od; 2: 200mg od; 3: 400mg od. Results: No DLTs were seen at dose level 1 or in the first 3 patients at dose level 2. 3 DLTs of grade 2 neuropathy were seen at dose level 3 (400mg taladegib); therefore, dose level 2 was expanded to 6 patients. No DLT was seen in the fourth patient and 2 additional patients have started treatment. After the DLT period 2 patients developed G2 and 4 developed G1 neuropathy. Other non DLT, drug-related G3 toxicities: uncomplicated neutropenia x2, muscle cramp x1 and fatigue x1. To date, 3 patients have had partial responses. Conclusions: The combination of daily oral taladegib and weekly paclitaxel is feasible. DLT of G2 neuropathy was seen at 400mg. Promising activity has been seen in solid tumours. A dose expansion cohort is due to commence in high grade ovarian carcinoma. ISRCTN No:ISRCTN15903698 Eudract Ref:2014-004695-37 Funded by Cancer Research UK C8361/A18775 and Ignyta. Sponsored by NHS Greater Glasgow and Clyde. Clinical trial information: ISRCTN15903698.

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A Phase 1 Study of Tasquinimod in Patients with Relapsed or Refractory Multiple Myeloma

Blood ◽

10.1182/blood-2020-137482 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 17-18

Author(s):

Dan T. Vogl ◽

Yulia Nefedova ◽

E. Paul Wileyto ◽

Harjeet Sembhi ◽

Inna Strakovsky ◽

...

Keyword(s):

Multiple Myeloma ◽

Adverse Events ◽

Dose Level ◽

Dose Escalation ◽

Research Funding ◽

Phase 1 ◽

Single Agent ◽

Optimal Schedule ◽

Study Endpoint ◽

Expansion Cohort

Background Multiple myeloma (MM) is a hematologic malignancy resulting from clonal proliferation of plasma cells in the bone marrow (BM). The BM tumor microenvironment confers therapeutic resistance through survival and growth signals to myeloma cells and suppression of anti-tumor immune responses. A population of myeloid-derived suppressor cells (MDSCs), abundantly producing the pro-inflammatory S100A9 protein, promotes myeloma progression. Tasquinimod (TASQ) is an investigational drug that targets MDSCs via the S100A9 protein. In pre-clinical models of MM, TASQ has significant anti-tumor effects as a single agent and in combination with bortezomib, a proteasome inhibitor (PI) and lenalidomide, an immunomodulator (IMiD) (Lin C, et al. 25th Annual Meeting of European Hematology Association June 11-21 2020: EP896). TASQ has previously been studied as a novel, once-daily oral anti-cancer agent, including in a phase-3 randomized trial in patients (pts) with metastatic prostate cancer that showed improvement in radiographic progression-free survival (Sternberg C, et al. JCO 2016; 34(22): 2636-43). The side effect profile of TASQ is well-characterized based on this previous experience. We therefore designed a phase 1 trial (NCT04405167) to establish the maximum tolerated dose (MTD) and optimal schedule for TASQ in MM and then investigate the MTD of TASQ in combination with a standard oral myeloma regimen of ixazomib, lenalidomide, and dexamethasone (IRd). For both single agent TASQ and the combination of TASQ with IRd, exploratory expansion cohorts will be enrolled to preliminarily characterize the antimyeloma activity of each regimen. Study Design Enrolled pts must have MM relapsed or refractory after at least one prior line of anti-MM therapy. Other key inclusion criteria include measurable disease and Eastern Cooperative Oncology Group performance status ≤2. Key exclusion criteria include failure to have fully recovered from clinically significant adverse effects of prior chemotherapy; active graft versus host disease; treatment with cytotoxic chemotherapy within 3 weeks prior to initiation of study treatment; treatment with PIs, IMiDs, or monoclonal antibodies within 2 wks, experimental therapy or plasmapheresis within 4 wks, or systemic corticosteroids or radiotherapy within 7 days; known central nervous system involvement by myeloma; or a diagnosis of smoldering MM or POEMS syndrome, active plasma cell leukemia, symptomatic primary amyloidosis, or myelodysplastic or myeloproliferative syndrome. Single agent TASQ and the combination of TASQ with IRd will be investigated in two parts. Part A will start with dose-escalation of single agent TASQ using a standard 3+3 design, with 3 to 6 pts evaluable for dose-limiting toxicity at each dose-level (see table). In the subsequent expansion cohort, additional pts will enroll at the MTD/optimal schedule, so that 12 pts total evaluable for response will have received the MTD/optimal schedule of single agent TASQ. Part B combines TASQ with standard-dose IRd: 28-day cycles of ixazomib 4 mg on days 1, 8, and 15, lenalidomide 25 mg on days 1-21, and dexamethasone 40 mg on days 1, 8, 15, and 22. The part B dose-escalation starts at the lower of either dose-level 1 or one dose-level below the single agent MTD. Additional pts with disease refractory to their most recent PI/IMiD combination will enroll into a part B expansion cohort, so that 12 pts total who are both evaluable for response and PI/IMiD refractory will have received the MTD/optimal schedule of TASQ in combination with IRd. Treatment will continue until unacceptable toxicity or myeloma progression. The primary study endpoint is the MTD of TASQ as single agent and in combination with IRd. Key secondary endpoints include toxicity (treatment-emergent grade 3/4 adverse events using the National Cancer Institute Common Toxicity Criteria for Adverse Events, version 5), preliminary antimyeloma activity (using the response criteria of the International Myeloma Working Group), changes in the BM microenvironment, and systemic TASQ exposure during therapy with single-agent TASQ and during therapy with TASQ in combination with IRd. These results will determine whether TASQ, alone or combined with standard anti-MM therapy, represents a promising novel treatment strategy in MM. Table 1 Disclosures Vogl: Active Biotech: Consultancy, Research Funding; Janssen: Consultancy; Karyopharm: Consultancy; Takeda: Consultancy; Celgene: Consultancy; Oncopeptides: Consultancy; MorphoSys: Consultancy. Nefedova:Active Biotech: Consultancy, Research Funding. Bondesson:Active Biotech: Current Employment. Eriksson:Active Biotech: Current Employment. Tuvesson:Active Biotech: Current Employment. OffLabel Disclosure: Tasquinimod for multiple myeloma

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A Phase I Study of GTI-2040, an Antisense to Ribonucleotide Reductase (RNR) in Combination with High-Dose Cytarabine (HiDAC) in Relapsed or Refractory Acute Myeloid Leukemia (AML): Pharmacokinetics (PK), Pharmacodynamic (PD) and Clinical Results.

Blood ◽

10.1182/blood.v106.11.2790.2790 ◽

2005 ◽

Vol 106 (11) ◽

pp. 2790-2790 ◽

Cited By ~ 2

Author(s):

Rebecca B. Klisovic ◽

W. Blum ◽

X. Wei ◽

S. Liu ◽

C. Kefauver ◽

...

Keyword(s):

Phase I ◽

Dose Level ◽

Dose Escalation ◽

Intermediate Risk ◽

Refractory Disease ◽

Phase Ii Trials ◽

Disease Response ◽

Level 1 ◽

Grade 3 ◽

Dna Incorporation

Abstract GTI-2040 is a 20-mer antisense to the R2 component of RNR mRNA. RNR is required for the conversion of ribonucleotides to deoxyribonucleotides, a crucial step during DNA synthesis and repair. Cytarabine (AraC) is a cytotoxic agent that is converted into AraC triphosphate (Ara-CTP) and is the backbone of several regimens in AML. Ara-CTP competes with deoxycytidine for DNA incorporation. We hypothesize that RNR downregulation by GTI-2040 results in decrease of levels of deoxycytidine thereby leading to a preferential DNA incorporation of ARA-CTP and increase in its cytotoxic activity. To test this hypothesis we undertook a CTEP-sponsored Phase I dose-escalation study of GTI-2040 plus HiDAC in patients (pts) with relapsed or refractory AML. Pts were stratified in 2 cohorts according to age. Cohort I (18–59 yrs) received escalating doses of GTI-2040 (dose level 1: 3.5 mg/m2/d) by continuous IV infusion (CIVI) on d 1–6 combined with escalating doses of cytarabine IV over 2 hrs q12 hrs on d 2, 4, and 6 (dose level 1: 2500 mg/m2/dose). Cohort II (≥60 yrs) received GTI CIVI on d 1–6 and cytarabine IV over 4 hrs on d 2 to 6 (dose level 1: 1500 mg/m2/d). To date, 30 pts were enrolled. Pts received median of 1 prior regimen (range 1–3). Cohort I included 8 pts with relapsed and 6 with refractory disease; 7 had intermediate risk cytogenetics (CyG) and 7 adverse CyG; 6 received prior HiDAC. Cohort II included 10 pts with relapsed and 6 with refractory disease; 8 pts had intermediate risk CyG and 8 high risk CyG; 5 pts received prior HiDAC. Toxicities were comparable to HiDAC therapy alone. Grade 3/4 non-hematologic toxicities included fatigue, fevers, anorexia, pneumonitis, and catheter related infections; a grade 3 reversible cerebellar toxicity (n=1) was observed at level 1/cohort I. An ELISA-based assay with a limit of quantification of 50 pMol was used to determine GTI2040 plasma and intracellular (IC) concentrations. Dose-dependent increase in plasma steady state concentration (Css) and area under the curve (AUC) of GTI2040 was observed in both cohorts, although higher AUC and longer t1/2 were demonstrated in the younger pts compared to the older ones. In cohort I, disease responses were seen at all dose levels Five of 14 pts achieved complete remission (CR) and one achieve incomplete CR (CRi; i.e., no marrow disease and incomplete blood count recovery). In cohort II, no disease response was observed. Median IC GTI2040 concentration in BM mononuclear cells at 120 hours following start of antisense infusion was higher in younger (i.e., 175 nM) than in older (i.e., 75 nM) pts. A median decrease in R2 protein levels of 50% (range 50–90%) detected by immunoblotting was noted in 5/9 and 5/10 pts in cohort I and II, respectively. In cohort I CR pts (n=4) had a median 50% decrease and non-responders (n=9) had a median 200% increase in R2 levels. In cohort II changes in R2 levels did not predict disease response. In summary, combination of GTI-2040/HiDAC is feasible. PK/PD studies demonstrate achievable plasma and IC levels of the antisense and target downregulation. Disease response was observed only with the dose/schedule administered to younger pts. Dose escalation in this group continues to establish a recommended dose for Phase II trials. [NCI U01 CA 76576-05].

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405 CDX1140–01, a phase 1 dose-escalation/expansion study of CDX-1140 alone (Part 1) and in combination with CDX-301 (Part 2) or pembrolizumab (Part 3)

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-sitc2020.0405 ◽

2020 ◽

Vol 8 (Suppl 3) ◽

pp. A430-A430

Author(s):

Rachel Sanborn ◽

Ralph Hauke ◽

Nashat Gabrail ◽

Mark O’Hara ◽

Nina Bhardwaj ◽

...

Keyword(s):

Dose Escalation ◽

Metabolic Response ◽

Phase 1 ◽

Safety Data ◽

Systemic Exposure ◽

University Of Pennsylvania ◽

Cancer Center ◽

Low Grade ◽

Metastatic Pancreatic Adenocarcinoma ◽

Expansion Cohort

BackgroundCDX-1140 is an agonist anti-CD40 mAb selected to optimize systemic exposure and hence tumor microenvironment (TME) ingress. CDX-1140 activity may be enhanced by combining with CDX-301 (recombinant Flt3L), a dendritic cell growth factor, or with pembrolizumab, an anti-PD-1 mAb.MethodsPatients with advanced solid or hematologic (Part 1 only) tumors are enrolled. Part 1 dose-escalation results have been presented (SITC 2019). In Part 2, CDX-1140 dose-escalation (0.09–1.5 mg/kg q4w) is in combination with CDX-301 (75 mcg/kg sc QD x 5 for 2 cycles). In Part 3, CDX-1140 dose-escalation (0.72–1.5 mg/kg q3w) is in combination with pembrolizumab 200 mg q3w. Part 1 and 2 expansion cohorts are dosed at the CDX-1140 MTD, 1.5 mg/kg q4w. Part 3 expansion cohorts are planned. Peripheral blood and tumor biomarkers analysis are ongoing.Results92 patients have been treated (Part 1 n=57, Part 2 n=31, Part 3 n=4). Part 1 expansion cohorts in SCCHN (n=7) and RCC (n=5) are fully enrolled. Part 2 dose-escalation completed to the highest CDX-1140 dose and a SCCHN expansion cohort is ongoing. Part 3 dose-escalation recently initiated. Safety data is available for 23 and 10 patients at the MTD in Part 1 and 2, respectively. In general, the safety profiles were similar, with arthralgia (52% vs. 50%), pyrexia (44% vs 50%), fatigue (30% vs. 50%), chills (39% vs. 40%), vomiting (30% vs. 20%), nausea (26% vs 40%), myalgia (22% vs. 30%), increased ALT (22% vs. 20%), and increased AST (22% vs. 30%) being the most common drug related AEs at the MTD in Part 1 and 2, respectively. Most AEs were low grade. Across all cohorts, cytokine release syndrome (CRS) (G2 n=4, G3 n=2) occurred in 6 (Part 1 n=2; Part 2 n=4) and pneumonitis (G3) occurred in 5 (Part 1 n=4; Part 2 n=1) patients. Immune activation in the TME consistent with CD40 agonism and increases serum inflammatory cytokines were observed. Evidence of anti-tumor activity/clinical benefit include SD (n=13), tumor cavitation (n=2) and a uPR in solid tumors. A patient with follicular lymphoma has an ongoing durable complete metabolic response.ConclusionsThe CDX-1140 MTD dose of 1.5 mg/kg, a dose level expected to provide good systemic exposure and TME penetration, is generally well tolerated alone and with CDX-301. Transaminitis and CRS have generally been low grade and infrequent. A cohort combining CDX-1140 with chemotherapy will be initiated in patients with previously untreated metastatic pancreatic adenocarcinoma.Trial RegistrationNCT03329950Ethics ApprovalThe study was approved by the following: Providence St. Joseph Health IRB, approval number MOD2020001128; WIRB, approval number 1188814 (Hauke, Gabrail, Bordoni & Gordon); University of Pennsylvania IRB, approval number UPCC 18917; Mount Sinai School of Medicine IRB, approval number 18-00202; Memorial Sloan Kettering Cancer Center IRB, approval number 18-225A; Houston Methodist IRB, approval number MOD00000836

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CTNI-15. CLINICAL EFFICACY OF ONC201 IN NEWLY DIAGNOSED DIPG AND IN PREVIOUSLY IRRADIATED PEDIATRIC H3 K27M-MUTANT GLIOMAS

Neuro-Oncology ◽

10.1093/neuonc/noaa215.182 ◽

2020 ◽

Vol 22 (Supplement_2) ◽

pp. ii45-ii45

Author(s):

Sharon Gardner ◽

Carl Koschmann ◽

Rohinton S Tarapore ◽

Jeffrey Allen ◽

Wafik Zaky ◽

...

Keyword(s):

Body Weight ◽

Single Agent ◽

Biologically Active ◽

Pharmacokinetic Analysis ◽

Low Grade ◽

Newly Diagnosed ◽

Liquid Formulation ◽

Phase Ii Trials ◽

Body Weights ◽

Post Radiation

Abstract ONC201, an anti-cancer DRD2 antagonist and ClpP agonist, is in Phase II trials for adult H3 K27M-mutant diffuse midline gliomas. In adults, the recommended phase 2 dose (RP2D) of 625mg ONC201 once a week has been established as a biologically active dose that is well tolerated. Radiographic regressions with single agent ONC201 have been reported in adult recurrent H3 K27M-mutant glioma patients. This multi-arm, dose-escalation and dose-expansion trial determined the pediatric RP2D of ONC201 administered as an oral capsule (Arm A) or liquid formulation (Arm E) in post-radiation H3 K27M-mutant glioma (Arm A) or in newly diagnosed DIPG (Arm B) patients. Molecular assessments include intratumoral ONC201 concentrations (Arm C) and CSF H3 K27M DNA levels (Arm D). Enrollment as of April 30, 2020 is complete in Arm A (22) and Arm E (26) and continues in Arm B (18/24), Arm C (5/12), and Arm D (22/24). The RP2D of weekly 625mg ONC201 scaled by body weight was confirmed when administered as a capsule or a liquid formulation as a single agent or in combination with radiation without dose-limiting toxicity. The most frequent adverse events regardless of attribution to the drug were predominantly low grade: ONC201 capsule alone was headache (54.5%), nausea (36.4%), and fatigue (36.4%); ONC201 liquid formulation was vomiting (31.8%), headache (22.7%), VIth nerve disorder (22.7%); ONC201 capsules in combination with radiation (Arm B) was headache (47.1%), vomiting (52.9%), nausea (41.2%). Pharmacokinetic analysis in plasma of Arm A patients revealed T1/2: 8.4h; Tmax: 2.1h; Cmax: 2.3ug/mL; AUC0-tlast: 16.4ug/mL, with similar exposure across body weights. In conclusion, when scaled by body weight the ONC201 capsule or liquid formulation alone or in combination with radiation were associated with safety and pharmacokinetic profiles in pediatric H3 K27M-mutant diffuse midline glioma patients that are similar to the experience in adults.

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Addition of Oxaliplatin to Continuous Fluorouracil, l-Folinic Acid, and Concomitant Radiotherapy in Rectal Cancer: The Lyon R 97-03 Phase I Trial

Journal of Clinical Oncology ◽

10.1200/jco.2001.19.9.2433 ◽

2001 ◽

Vol 19 (9) ◽

pp. 2433-2438 ◽

Cited By ~ 82

Author(s):

Gilles Freyer ◽

Nadine Bossard ◽

Pascale Romestaing ◽

Françoise Mornex ◽

Olivier Chapet ◽

...

Keyword(s):

Rectal Cancer ◽

Phase I ◽

Folinic Acid ◽

Dose Level ◽

Dose Escalation ◽

Local Treatment ◽

Rectal Adenocarcinoma ◽

Severe Diarrhea ◽

Phase Ii Studies ◽

Level 1

PURPOSE: Oxaliplatin could increase the efficacy of fluorouracil (5-FU)/folinic acid chemoradiotherapy in rectal cancer. We tested three dose levels to identify a feasible oxaliplatin dose for combination therapy. PATIENTS AND METHODS: Between February 1998 and April 2000, we included 17 rectal adenocarcinoma patients in a single-center phase I study. Patients had T4 rectal carcinoma, T1-T3 disease with colostomy refusal, or potentially operable T2/T3 M1 requiring local treatment. Pelvic radiotherapy was 45 Gy over 5 weeks, 1.8 Gy/fraction, with concomitant chemotherapy weeks 1 and 5. Chemotherapy was oxaliplatin 80, 100, or 130 mg/m2 2-hour infusion on day 1 followed by l-folinic acid 100 mg/m2/d intravenous bolus, and 5-FU 350 mg/m2/d continuous infusion on days 1 to 5 (FolfoR1). Six patients refusing surgery received additional contact radiotherapy +/− brachytherapy. Dose escalation proceeded if less than two of six patients had dose-limiting toxicity (DLT) at a given dose-level. RESULTS: All except two patients completed treatment; patients at level 1 (prolonged grade 1 thrombocytopenia) and level 3 (prolonged cold-related dysesthesia) had no second chemotherapy course. Median follow-up is 14 months (range, 2 to 28 months). One elderly patient at dose level 1 had DLT asthenia, severe diarrhea and vomiting, and more than 10% weight loss. There were no other DLTs and no severe rectitis or gastrointestinal toxicity. There were objective responses at all doses and no progressions. Eight patients underwent radical surgery after chemoradiotherapy. Two had complete pathologic responses. CONCLUSION: FolfoR1 seems feasible and effective. Dose escalation did not increase toxicity. Although the MTD was not reached in this study, we recommend oxaliplatin 130 mg/m2 for phase II studies because it is the dose determined from studies in metastatic patients with no toxicity when given concurrently with radiation.

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ACTR-63. PHASE I DOSE ESCALATION STUDY OF PROCASPASE ACTIVATING COMPOUND-1 (PAC-1) IN COMBINATION WITH TEMOZOLOMIDE IN PATIENTS WITH RECURRENT ANAPLASTIC ASTROCYTOMA OR GLIOBLASTOMA

Neuro-Oncology ◽

10.1093/neuonc/noz175.105 ◽

2019 ◽

Vol 21 (Supplement_6) ◽

pp. vi28-vi28

Author(s):

Matthias Holdhoff ◽

Martin Nicholas ◽

Richard Peterson ◽

Oana Danciu ◽

Stefania Maraka ◽

...

Keyword(s):

Dose Level ◽

Dose Escalation ◽

Anaplastic Astrocytoma ◽

Caspase 3 ◽

Phase 1 ◽

Maximum Tolerated Dose ◽

Pharmacokinetic Data ◽

Dose Escalation Study ◽

Level 1 ◽

Level 2

Abstract BACKGROUND Procaspase activating compound -1 (PAC-1) is a small molecule that catalyzes conversion of procaspase-3 to caspase-3 which induces apoptosis in cancer cells. Glioblastoma (GBM) is among the tumors with high concentrations of procaspase-3 and low levels of caspase-3. PAC-1 crosses the blood brain barrier and has been shown to synergize with temozolomide (TMZ) in canine malignant glioma and meningioma that arise spontaneously. METHODS This is a multicenter phase 1 dose-escalation study to assess the maximum tolerated dose (MTD) of PAC-1 administered days 1–21 in combination with TMZ days 8–12 at a dose of 150 mg/m2 of each 28 day cycle in subjects with recurrent anaplastic astrocytoma (AA) or GBM. A modified Fibonacci 3 + 3 design is used with up to 4 dose levels of PAC-1 (375, 500, 625 and 750 mg/day). Neurologic toxicity, including cognitive function, is closely monitored throughout the trial. INTERIM DATA: A total of 14 subjects have been enrolled to-date. Of these, 7 at dose level 1, PAC-1 375 mg/day (6 GBM, 1 AA; median age 58y, range 25–75) and 7 at dose level 2, PAC-1 500 mg/day (5 GBM, 2 AA; median age 51y, range 35–60). Best responses to-date were 2 subjects with a partial response and 2 with stable disease. Grade 3 (hepatotoxicity) and 4 (cerebral edema) was reported as possibly related to PAC-1 in 1 patient at dose level 1. The median number of cycles received was 4 (range, 1–12+) at dose level 1 and 2 (range, 1–3) at dose level 2. Enrollment to dose level 2 has been completed and data analysis is ongoing. Updated response and toxicity as well as pharmacokinetic data will be presented.

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Lenalidomide, Bortezomib, and Dexamethasone (Rev/Vel/Dex) as Front-Line Therapy for Patients with Multiple Myeloma (MM): Preliminary Results of a Phase 1/2 Study.

Blood ◽

10.1182/blood.v110.11.187.187 ◽

2007 ◽

Vol 110 (11) ◽

pp. 187-187 ◽

Cited By ~ 5

Author(s):

Paul Richardson ◽

Sundar Jagannath ◽

Noopur Raje ◽

Andrzej Jakubowiak ◽

Sagar Lonial ◽

...

Keyword(s):

Dose Level ◽

Phase 1 ◽

Single Agent ◽

Safety Data ◽

High Dose ◽

Hematologic Toxicity ◽

Newly Diagnosed ◽

Front Line ◽

Dose Levels ◽

Dose Reductions

Abstract Background: Bortezomib (VELCADE®, Vel) as a single agent and lenalidomide (Revlimid®, Rev) plus dexamethasone (Dex) are approved for the treatment of relapsed MM patients (pts) following ≥1 prior therapy. Rev/Vel±Dex is active and well tolerated in relapsed/refractory MM, and Rev/Dex and Vel/Dex have substantial activity in front-line MM. The aims of this phase 1/2 study were to determine the MTD of Rev/Vel/Dex in newly diagnosed MM pts, and to assess safety and efficacy. Methods: Pts received Rev 15–25 mg on d 1–14, Vel 1.0–1.3 mg/m2 on d 1, 4, 8, 11, and Dex 40/20 mg (cycles 1–4/5–8) on d 1, 2, 4, 5, 8, 9, 11, 12, for up to 8 21-d cycles, initially at 4 planned dose levels (Rev/Vel: 15/1.0, 15/1.3, 20/1.3, 25/1.3). Dose escalation proceeded (3-pt cohorts) depending on DLTs (G≥3 non-hematologic toxicity; G4 thrombocytopenia with platelets <10,000/mm3 on >1 occasion despite transfusion support; G4 neutropenia for >5 d and/or resulting in neutropenic fever; inability to receive cycle 2/d 1 dose due to drug-related toxicity). Based on safety data, dose level 4M was added with a reduced Dex starting dose (Rev/Vel 25/1.3, Dex 20 mg in all cycles). Toxicities were graded by NCI CTCAE v3.0. Pts with G>2 peripheral neuropathy (PNY) were excluded. Responses were assessed by modified EBMT and Uniform criteria. Pts with CR/nCR/VGPR/PR could proceed to ASCT after ≥4 cycles. Results: 33 pts (median age 56 yrs, 55% men, 84% IgG MM, 47% with ISS Stage II/III) have been enrolled to date in dose levels 1–4 and 4M, respectively, including 10 pts enrolled at the maximum planned dose (Dose Level 4M). Pts have received a median of 5 cycles; 9 pts have completed all 8 cycles. Two DLTs of G3 hyperglycemia due to high dose Dex were seen in dose level 4. Dose reductions in cycle 2 and beyond have occurred in dose levels 1–4 for Rev in 9 pts, Vel in 7 pts, and Dex in 17 pts, with 3 dose reductions having occurred in dose level 4M. Toxicities to date have been manageable. Only 1 G4 toxicity (thrombocytopenia) has been reported, plus 1 G3 DVT (reversed with LMWH), and no G≥3 PNY has been seen. The response rate across all dose cohorts (CR/nCR+VGPR+PR: subject to confirmation) is currently 89% in 25/28 evaluable pts, including 35% CR/nCR/VGPR. After median follow-up of 3 mos, median DOR, TTP, PFS, and OS have not been reached; all responders except 1 remain in remission, with 2 pts proceeding to ASCT. Conclusions: Rev/Vel/Dex is very active and well tolerated in newly diagnosed MM pts. The maximum planned dose has been reached at Rev 25 mg, Vel 1.3 mg/m2, and Dex 20 mg, with Phase 1 enrollment now complete using the lower dose of Dex. Enrollment to the Phase 2 component is ongoing.

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Novel Monoclonal Antibody Enhances Natural Killer (NK) Cell Cytotoxicity against Multiple Myeloma (MM): Interim Phase 1 Trial Results.

Blood ◽

10.1182/blood.v114.22.2880.2880 ◽

2009 ◽

Vol 114 (22) ◽

pp. 2880-2880

Author(s):

Don Benson ◽

Craig C. Hofmeister ◽

Swaminathan Padmanabhan ◽

Rafat Abonour ◽

Attaya Suvannasankha ◽

...

Keyword(s):

Tumor Cells ◽

Dose Escalation ◽

Nk Cell ◽

Biological Effects ◽

Single Agent ◽

Safety Data ◽

Cell Maturation ◽

Cell Cytotoxicity ◽

Study Results ◽

Nk Cell Cytotoxicity

Abstract Abstract 2880 Poster Board II-856 Background: MM is increasing in incidence and remains incurable. .NK cells have modest killing activity against MM tumor cells in part because of inhibitory KIR receptors which recognize HLA class 1 antigens on MM tumor cell targets. However, experimental and clinical data in the allogeneic transplant setting suggest that NK cell stimulation by a mismatch between donor KIR and patient KIR ligand may improve outcomes for MM after a reduction of tumor burden by previously administered treatments. To mimic this effect with a pharmaceutical agent, 1-7F9/IPH2101, a fully human IgG4 anti-KIR mAb specific for KIR2DL1/2/3 (HLA-C specific KIRs) was generated (Romagne et al., Blood June, 2009). 1-7F9/IPH 2101 enhances patient NK cell cytotoxicity against autologous MM tumor cells in vitro. We present the interim results of the human phase I trial of this agent in patients with relapsed/refractory MM. Methods: An open-label, single-agent, dose-escalation, multiple dose safety and tolerability study of IPH2101 is being conducted in heavily pre-treated patients with relapsed/refractory MM. Dose escalation with IPH2101 (0.0003, 0.003, 0.015, 0.075, 0.3, 1, 3 mg/kg as IV infusion) is being studied using a 3+3 scheme. Re-dosing criteria (1/month x 4 months) are based on safety data from previous dosing. KIR occupancy, pharmacokinetics (PK), pharmacodynamics, effects on NK cell maturation, and biological effects of IPH 2101 are being monitored in all patients. Results: Currently, dose escalation is entering the final (3 mg/kg) cohort. Data from the first 22 treated patients are available. No Dose Limiting Toxicity (DLT) has been observed. 1 pt (at DL1) has been replaced and 3 additional pts have been enrolled (at DL4) due to an SAE an acute renal failure possibly related to drug. Related Adverse Events were seen in 4/22 patients (18%). 12/22 pts received at least 2 doses (6pts had 2, 1 pt had 3 and 5 pts had 4 cycles-median 2). KIR full occupancy (> 90%) for at least 3 weeks is reached at 1mg /kg. In accordance with the pre-clinical PK/PD model there is a clear relationship between exposure (Cmax) and KIR occupancy. No deleterious effect on NK cell maturation has been seen. IPH 2101 has been well tolerated to date. In the cohorts accrued to date, two heavily pre-treated patients, both with high-risk cytogenetics, showed evidence to suggest disease stabilization while receiving IPH-2101. Conclusions: IPH 2101 improves autologous NK cell killing of MM tumor cells by blocking inhibitory KIR. In the on-going clinical trial, the antibody appears safe and well tolerated at the doses tested. Updated study results will be presented at the time of the meeting This immunotherapeutic approach may hold promise as treatment for MM and further study is warranted. Disclosures: Squiban: Innate pharma: Employment. Marzetto:Innate Pharma: Employment. Andre:Innate Pharma: Employment. Tollier:Innate Pharma: Employment.

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