A phase I study of R-(-)-gossypol (AT-101) in combination with cisplatin (P) and etoposide (E) in patients with advanced solid tumors and extensive-stage small cell lung cancer (ES-SCLC)

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e13502-e13502
Author(s):  
T. B. Leal ◽  
W. Schelman ◽  
A. Traynor ◽  
J. Kolesar ◽  
R. Marnosha ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Dose Level ◽  
Unknown Primary ◽  
Clinical Activity ◽  
Dose Escalation Study ◽  
Objective Evidence ◽  
Level 1 ◽  
Grade 3

e13502 Background: AT-101 [R-(-)-gossypol acetic acid] (AT) is an orally-administered BH3 mimetic that lowers the threshold for apoptosis by direct binding to Bcl-2, Bcl-xL, Mc1–1, Bcl-W, and through upregulation of the proapoptotic proteins Noxa and Puma. Bcl- 2 is over-expressed in >80% of SCLC. In vitro study using SCLC cells showed that treatment with EP had synergistic cytotoxic effects in suppression of Bcl-2. This is a phase I dose-escalation study of AT in combination with EP with an expanded cohort of patients with ES-SCLC. This study is being conducted to determine the maximum tolerated dose (MTD), pharmacokinetics and activity of AT with EP ± pegfilgrastim (F) in patients with advanced, refractory solid tumors and/or ES-SCLC. Methods: This study used standard eligibility criteria except patients must not have received prior therapy that inhibits the Bcl-2 family. At dose level 1, patients received P 60 mg/m2 on day 1 and E 100 mg/m2 on days 1, 2, and 3 every 21 days. AT was administered 30 mg orally BID on days 1, 2 and 3 of each cycle. Results: 10 patients have been enrolled; 7 men, 3 women. Tumor types: 6 lung; 2 prostate; 1 head & neck; 1 unknown primary. 2 of 5 patients enrolled at dose level 1 experienced a DLT of neutropenic fever in cycle 1. Three subsequent patients were enrolled to dose level -1 (20 mg BID x 3 days, d1–3) which was well tolerated. Additional patients are being enrolled at dose level 1a (EP+AT with F). Grade 3/4 toxicities related to AT without F at dose level 1 and -1 were as follows: ANC (8), leucopenia (7), febrile neutropenia (2), low hemoglobin (1), thrombocytopenia (1), elevated AST (1), cardiac ischemia/MI (1), diarrhea (1). There were no reported grade 3/4 toxicities in two patients at level 1a. Four patients had stable disease; two progressive disease and four patients were unevaluable. Conclusions: The MTD without F was established at AT 20mg orally BID, P 60 mg/m2 on day 1, and E 100 mg/m2 on days 1, 2, and 3 every 21 days. The MTD with F has not yet been established. Accrual continues at dose level 1a. Subjective and objective evidence of clinical activity has been observed in patients with refractory solid tumors. This study was supported by NCI, UO1 CA062491, SAIC 25XS097 and 1ULRR025011. No significant financial relationships to disclose.

Phase I trial of metronomic cyclophosphamide (CTX) and lenalidomide (LEN) in patients with castration-resistant prostate cancer (CRPC).

2012 ◽  
Vol 30 (5_suppl) ◽  
pp. 164-164
Author(s):  
Jue Wang ◽  
Timothy R. McGuire ◽  
James K. Schwarz ◽  
Jane L Meza ◽  
James E E Talmadge
Keyword(s):  
Phase I ◽  
Dose Level ◽  
Performance Status ◽  
Patient Characteristics ◽  
Maximum Tolerated Dose ◽  
Clinical Activity ◽  
Castration Resistant Prostate Cancer ◽  
Ecog Performance Status ◽  
Level 1 ◽  
Grade 3

164 Background: Angiogenesis and suboptimal antitumor immune response are important in the progression of CRPC. Both LEN and metronomic CTX have known anti-angiogenic and immunomodulatory activities. A phase I study of a novel combination of metronomic CTX with LEN in patients with CRPC who have failed prior docetaxel therapy was initiated to assess safety and effects on potential biomarkers. Methods: CTX was given 50 mg PO QD(day 1-28) and LEN 10-25 mg PO QD(day 1-21) on a 28 day cycle. Dose limiting toxicity was defined as any treatment-related grade 4 hematologic event or grade 3 / 4 non-hematologic event during cycles one. Quantification of circulating tumor cells (CTC), plasma cytokines, analgesic consumption and quality of life assessments were performed. Measurement of Treg and MDSCs were performed in some patients. Results: 17 patients with CRPC have been enrolled in L0-4; all patients are evaluable for toxicity. Patient characteristics include: ECOG performance status 0/1= 4/13; median age=77 (range 50–86); median PSA=36.7 (range 1.36–2287). Dose level 1 (CTX 50 mg/d, LEN 10 mg/d) was expanded to 6 patients after one out of three initial patients was removed from the study for Gr 3 gastrointestinal bleeding (in cycle 1). Dose level 1 (CTX 25 mg/d, LEN 10 mg/d) had no DLT’s. The maximum tolerated dose has not yet been reached. Other Grade 3/4 toxicities observed after cycle 1 included grade 3 pain (N=1), grade 3 neutropenia (N=4), grade 3 thrombocytopenia (N=2), grade 4 neutropenia (N=2). Most frequent grade 1 and 2 toxicities included anemia, fatigue, neutropenia, and hypocalcemia. Overall, 9 of 14 patients (64%) have experienced a reduction in PSA. One patient had partial response after one cycle. Stable disease was documented in 5 of 14 (36%) evaluable patients. Two inflammatory cytokines, IL-6 (N = 19; r = 0.64; p = 0.0035) and IL-8 (N = 9; r = 0.86; p = 0.0028), were found to significantly correlated with PSA. Conclusions: The combination of metronomic CTX and LEN can be safely administered. Preliminary clinical activity was observed in this heavily-pretreated patient population. Enrollment to this study continues and clinical and biomarker studies are ongoing.

Pooled analysis of phase I dose-escalation and dose cohort expansion studies of IMP4297, a novel PARP inhibitor, in Chinese and Australian patients with advanced solid tumors.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 3059-3059 ◽  
Author(s):  
Junning Cao ◽  
Pin Zhang ◽  
Paul L. de Souza ◽  
Bo Gao ◽  
Mark Voskoboynik ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Dose Level ◽  
Dose Escalation ◽  
Single Agent ◽  
Response To Treatment ◽  
Clinical Activity ◽  
Dose Cohort ◽  
Phase Ii Studies ◽  
Grade 3

3059 Background: Poly (ADP-ribose) polymerase (PARP) enzymes play critical roles in DNA damage detection and repair. IMP4297 is a novel, potent PARP1/2 inhibitor (IC50 6.27nM/1.57nM) and has demonstrated to be 20-fold more potent than Olaparib in anticancer animal models. Two phase I studies were performed to evaluate and characterize the tolerability and safety, pharmacokinetics, and antitumor activity of single agent IMP4297 in Chinese and Australian patients with advanced ovarian, breast, prostate and other solid tumors. Methods: Dose escalation used a 3+3 design with a modified Fibonacci escalation. Dose cohort expansion was planned after efficacy was observed at the lowest dose level. Patients received IMP4297 monotherapy orally once a day until disease progression or unacceptable toxicity. Results: As of Jan 12, 2019, 56 patients, including 23 BRCA mutation carriers (BRCA+), had been enrolled at 2-100 mg dose level. No DLT was observed. In these two studies, the most frequent treatment-related adverse events (TRAEs) were leukopenia (20%), followed by anemia (18%), nausea (18%) and thrombocytopenia (14%). The majority of TRAEs were grade 1 or 2. Grade 3 TRAEs occurred in five patients (anemia, n=2; vomiting, n=1; thrombocytopenia, n=1; elevated AST, n=1). Only one patient had a dose reduction due to grade 3 thrombocytopenia. No serious TRAEs were observed. In 15 BRCA+ patients who had measurable lesions, the ORR was 33% and the DCR was 80%. There were 4 BRCA+, platinum-sensitive ovarian cancer patients with an ORR of 75% and a DCR of 100%. One patient with somatic BRCA mutated urothelial carcinoma showed a 76% decrease in tumor size. Conclusions: IMP4297 has been well-tolerated with significant anti-tumor activity. The 100 mg daily dose was selected as the RP2D based on safety, pharmacokinetics and clinical activity, and will be further characterized in dose expansion and phase II studies. Tumor response to treatment (RECIST 1.1) in patients with measurable lesions. Clinical trial information: NCT03508011 and NCT03507543. [Table: see text]

Phase I study of obatoclax mesylate (GX15–070MS), a bcl-2 antagonist, plus topotecan in relapsed small cell lung carcinoma and other solid tumors

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 3504-3504
Author(s):  
A. B. Brown ◽  
C. Rudin ◽  
N. Rizvi ◽  
W. Travis ◽  
N. Takebe ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Phase Ii ◽  
Small Cell Lung Carcinoma ◽  
Small Cell ◽  
Clinical Activity ◽  
Hematologic Toxicity ◽  
Dose Escalation Study ◽  
Cell Lung Carcinoma ◽  
Grade 3

3504 Background: Bcl-2 is a rational target in SCLC since it is overexpressed in 60%-90% of tumors and may play a role in resistance of SCLC to chemotherapy. Obatoclax is a small molecule BH3 mimetic that blocks bcl-2 binding to proapoptotic family members. Obatoclax has growth inhibitory effects in several solid tumor cell lines and xenografts, with at least additive effects in combination with topotecan. The primary objective of this study was to evaluate the safety profile and maximum tolerated dose (MTD) of obatoclax plus topotecan in patients with relapsed SCLC and other solid tumors. Methods: We conducted a phase I dose escalation study using a standard “3+3” design. Obatoclax was administered at 14 or 20 mg/m2 over 3 hours on day 1 every 21 days. A subsequent cohort received obatoclax 14mg/m2 on days 1 and 3. Topotecan was given at 1.25 mg/m2 days 1–5. All patients received pegfilgrastim on day 8. Eligible patients were adults with solid tumors appropriate for treatment with topotecan. Patients with neurologically stable, treated brain mets were eligible. Results: 14 patients have been treated including 8 SCLC, 3 extrapulmonary small cell, 1 carcinoid, 1 Merkel cell and 1 melanoma previously treated with 1 or 2 lines of chemotherapy. Nearly all patients experienced neurologic toxicities during the obatoclax infusion which included ataxia, dysarthria, somnolence and/or mood alteration; these typically resolved 1–2 hours after completion of the infusion. The MTD of obatoclax was 20 mg/m2 on day 1 with Dose Limiting Toxicities (DLT) including grade 3 neurotoxicity (2 pts) and febrile neutropenia. Hematologic toxicity included grade 3/4 anemia (6 pts), thrombocytopenia (5 pts) and neutropenia (5 pts). Other toxicities included mild nausea/vomiting, fatigue, pruritus, and constipation. Clinical activity was seen in patients with SCLC including 1 PR and 4 SD out of 7 evaluable. The median TTP for these SCLC patients was 11 weeks. Conclusions: The recommended phase II dose is obatoclax 14 mg/m2 on days 1 and 3 with topotecan 1.25 mg/m2 on days 1–5 in 21 day cycles. A phase II study in second-line SCLC is open. Supported by NCI U01-CA69856. No significant financial relationships to disclose.

Phase I trial of cabazitaxel plus cisplatin in patients with advanced solid tumors.

2012 ◽  
Vol 30 (5_suppl) ◽  
pp. 162-162 ◽  
Author(s):  
Albert C. Lockhart ◽  
Shankar Sundaram ◽  
John Sarantopoulos ◽  
Monica M. Mita ◽  
Alex R. Lane ◽  
...  
Keyword(s):  
Febrile Neutropenia ◽  
Phase I ◽  
Solid Tumors ◽  
Dose Level ◽  
Combined Treatment ◽  
Primary Objective ◽  
Phase Iii ◽  
Clinical Activity ◽  
Primary Tumors ◽  
Grade 3

162 Background: Cabazitaxel (Cbz) is a novel taxane with broad in vivo efficacy in taxane-sensitive and -resistant tumors. Clinical activity of Cbz was confirmed in the Phase III TROPIC trial ( NCT00417079 ); Cbz significantly improved overall survival compared with mitoxantrone in patients (pts) with metastatic castration-resistant prostate cancer whose disease had progressed during or after a prior docetaxel-containing regimen. Therapeutic synergism of Cbz/cisplatin (Cis) has been demonstrated in tumor-bearing mice. Methods: The primary objective in part 1 of this Phase I study ( NCT00925743 ) was to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of Cbz/Cis. Secondary objectives were safety, pharmacokinetics (PK) and efficacy. The primary objective of part 2 was to determine the antitumor activity at the MTD. Eligible pts were ≥ 18 yrs, ECOG PS ≤ 1, with confirmed metastatic or unresectable solid tumors for which Cis therapy was considered appropriate. A 3 + 3 dose escalation with a starting dose (level 0) of 20/75 mg/m2 (Cbz/Cis), administered IV Q3W, was used. The MTD was the highest dose at which 0/3 or ≤ 1/6 pts experienced a DLT in Cycle 1. Results: Pts (N = 25; 10 in part 1; 15 in part 2) with a median age of 56 yrs were enrolled. The most frequent primary tumors were lung (n = 4), prostate, ovary and pancreas (each n = 2). 2 of 6 evaluable pts experienced a DLT at dose level 0 (Grade 3 acute renal failure; febrile neutropenia). The MTD was 15/75 mg/m2 as no DLTs were observed. Eighteen pts were treated at the MTD and 60 cycles were administered (median = 3; range 1–8). The most frequent non-hematologic treatment-related adverse events (all Grade/Grade 3–4) were nausea (78%/22%), vomiting (72%/11%), fatigue (61%/17%), anorexia (67%/11%) and diarrhea (44%/0%). Incidence of Grade 3–4 neutropenia was 78% and 1 pt had febrile neutropenia. No PK interactions between Cbz and Cis were observed. Stable disease was seen in 11 pts. No objective responses were reported. Conclusions: The MTD of Cbz/Cis was 15/75 mg/m2. The combination had a manageable safety profile consistent with that of a platinum/taxane combination. No PK interactions were seen. Further investigations into the combined treatment combination are planned.

Phase I/II Study of Bortezomib in Combination with Liposomal Doxorubicin and Melphalan in Relapsed or Refractory Multiple Myeloma.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 5182-5182 ◽  
Author(s):  
Ajai Chari ◽  
Lawrence Kaplan ◽  
Charles Linker ◽  
Lloyd E. Damon ◽  
Willis H. Navarro ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Level ◽  
Dose Escalation ◽  
Progressive Disease ◽  
Liposomal Doxorubicin ◽  
Maximum Tolerated Dose ◽  
Dose Escalation Study ◽  
Heavily Pretreated ◽  
Level 1 ◽  
Grade 3

Abstract Phase I/II studies using either liposomal doxorubicin (D) or oral melphalan (M) in combination with the proteasome inhibitor bortezomib (V) have found favorable efficacy and tolerance in patients with relapsed and refractory MM. Since these drugs have different mechanisms of action and toxicity profiles, we initiated a phase I/II study to examine the safety and efficacy of combining all three agents (DMV) in relapsed or refractory myeloma. Study Aims: Starting at 25–50% of the doses used in the two drug combination studies, the objective of this dose escalation study was to evaluate the safety/tolerability of DMV until the maximum tolerated dose (MTD) and dose limiting toxicity (DLT) could be identified. Efficacy was also evaluated. Methods: Patients with relapsed/refractory MM and progressive disease requiring treatment were enrolled in the study. Dose level 1 consisted of D 10 mg/m2 and M 5 mg/m2 given IV on day 1 with V given by IV push on days 1, 4, 8, and 11. Cycles were repeated every 28 days up to a maximum of 6 cycles. Dose levels of D, M, V (mg/m2) in the subsequent three cohorts were (10, 10, 0.7), (20, 10, 0.7), and (20, 10, 1.0) respectively. Once the MTD has been identified, an additional 17 patients will be enrolled at this dose level in the phase II portion of the study. Results: 5 patients (2 males, median age 65, range 33–79) have been enrolled in the study thus far. The myeloma subtypes include 2 IgG, 1 IgA, and 2 with light chains only. In this heavily pretreated population (range 2–7 prior therapies), 4 patients received prior autologous stem cell transplantation, 2 had a prior nonmyeloablative allogenic transplant, 4 prior VAD, 1 prior bortezomib, 2 prior oral melphalan, 3 prior thalidomide, 2 prior CC-5013, and 2 prior spinal radiation. The first dose cohort has been completed without any DLT. One patient had 3 days of Grade 3 neutropenia. All other toxicities were Grade 1–2 including asthenia, vomiting, thrombocytopenia, and headache. Of note, a patient with baseline Grade 2 peripheral neuropathy and on hemodialysis remained stable. A patient with Grade 2 chronic graft versus host disease also remained stable. Four patients have been enrolled at dose level one. One patient, who had progressive disease after an autologous and a nonmyeloablative allogenic transplant as well as CC5013, had a near CR (IFE+) after the second cycle of DMV. Two patients have had stable disease. One had disease progression after one cycle and subsequently died. The patient on dose level two is too early to evaluate. Conclusion: Thus far, DMV appears to be well tolerated and no DLT has been observed even in elderly patients with significant comorbidities. The finding of a near CR and SD at only dose level 1 is encouraging particularly since the patients were significantly pretreated. Dose escalation continues to determine the MTD.

A phase I study of vorinostat in combination with bortezomib in refractory solid tumors

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 3573-3573 ◽  
Author(s):  
W. R. Schelman ◽  
J. Kolesar ◽  
K. Schell ◽  
R. Marnocha ◽  
J. Eickhoff ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Solid Tumors ◽  
Dose Level ◽  
Treatment Plan ◽  
Hdac Inhibitors ◽  
26S Proteasome ◽  
Clinical Activity ◽  
Eligibility Criteria ◽  
Objective Evidence ◽  
Level 1

3573 Background: Vorinostat (suberoylanilide hydroxamic acid, SAHA) is a histone deacetylase (HDAC) inhibitor that has anti- tumor activity in hematologic malignancies and advanced solid tumors. Based on studies showing that HDAC inhibitors increase the activity of the 26S proteasome, vorinostat has been postulated to act synergistically with bortezomib. This study was conducted to determine the toxicities and efficacy of vorinostat with bortezomib. Correlative studies included pharmacokinetics and the effects of vorinostat/bortezomib on cell cycle, proteasome inhibition, histone acetylation, gene expression and apoptosis. Methods: This study used standard eligibility criteria except pts must have had no prior bortezomib. The treatment plan consisted of vorinostat given orally on days 1–14 with bortezomib IV on days 1, 4, 8 and 11 of a 21-day cycle. Starting dose (Step A, level 1) was once-daily vorinostat (400 mg) and bortezomib (0.7 mg/m2). Step B consisted of twice-daily dosing of vorinostat (200mg) with bortezomib at MTD established in Step A. RECIST was used to measure response. Effects on G2/M-phase arrest in buccal mucosa cells (BMC) were measured using flow cytometry. Samples were collected on days 1 and 9, at 0, 2 and 4 hr following treatment. Results: 22 pts have been enrolled; 14 men, 8 women. Tumor types: 5 sarcoma, 5 colorectal, 3 pancreatic, 2 lung, 1 breast, 1 ovarian, 1 bladder, 1 gastric, 1 germ cell, 1 mesothelioma, 1 GIST. Grade 3–4 toxicities at least possibly related to vorinostat at any dose level were as follows: fatigue (3), n/v (1), thrombocytopenia (1), and hyponatremia (1). One pt was unevaluable. DLTs included fatigue (3), hyponatremia (1) and elevated ALT (1). The MTD for Step A was established at vorinostat 400mg daily and bortezomib 1.3 mg/m2. One pt with refractory soft tissue sarcoma had a PR > 9 mo. There was no effect on cell cycle arrest observed with vorinostat in BMCs. Conclusions: The MTD for Step A was established at vorinostat 400mg daily and bortezomib 1.3 mg/m2. Accrual continues at Step B, dose level 1. Subjective and objective evidence of clinical activity has been observed in pts with refractory solid tumors. (Supported by NCI grant UO1 CA062491, NCI SAIC contract 25XS097 and GCRC M01 RR03186.) No significant financial relationships to disclose.

Deflexifol (a novel formulation of 5FU): Phase 1 dose escalation study of infusional and bolus schedules after failure of standard treatment.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 2529-2529
Author(s):  
Philip R. Clingan ◽  
Stephen P. Ackland ◽  
Marie Ranson ◽  
Daniel Brungs ◽  
Morteza Aghmesheh ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Level ◽  
Dose Escalation ◽  
Standard Treatment ◽  
Phase 1 ◽  
Liver Function Tests ◽  
Clinical Activity ◽  
Dose Escalation Study ◽  
Advanced Malignancy ◽  
Grade 3

2529 Background: 5-Fluorouracil (5FU) is administered in combination with leucovorin (LV) to enhance clinical activity. However, simultaneous administration is not feasible as 5FU and LV are chemically incompatible, so the maximum possible interaction for benefit is not achieved Deflexifol, an all in one formulation of 5FU/LV with cyclodextrin (HP-β-CD 100mg/ml, 5-FU 15mg/ml & LV 1mg/ml) at physiological pH, was developed to improve efficacy and tolerance. Methods: A phase I dose-escalation trial to assess the safety, tolerability, MTD and DLT of Deflexifol given in two schedules has been completed. Secondary objectives included the pharmacokinetic (PK) profile and efficacy outcomes. Cohorts of patients with advanced malignancy after failure of standard treatment received Deflexifol as 46-h infusion Q2W or bolus weekly x6 in a standard 3+3 phase I design with no intra-patient dose escalation from dose level 1: 375mg/m² bolus or 1200mg/m² infusional up to dose level 5: 575mg/m² bolus or 3600mg/m² infusional. PK sampling of 5FU and dihydroFU was conducted on all patients to assess PK variability and adequacy of dosing. Results: 40 patients (21 infusional, 19 bolus) with breast (7), colorectal (24), other GI (6) & NSCLC (3) received a total 293 courses of treatment. No > grade 1 toxicity was noted at 375-475 mg/m2 bolus, or at 1200-2400 mg/m2 infusion. The DLT in bolus schedule was grade 3 diarrhea and myelosuppression at 575 mg/m2, with no DLT in the infusion schedule at the maximum dose 3600 mg/m2. The MTD have been established for both treatment arms: bolus 525mg/m²; 46-h infusion 3,600mg/m², with no grade IV toxicity observed. Other grade 3 toxicities were nausea, vomiting, and raised liver function tests. 5FU PK in this mixture is similar to 5FU alone. Encouraging efficacy results were seen with partial response in 1 patient and stable disease in 23 patients. Median PFS was (12.3 wks) and OS was (24.8 wks). Conclusions: Deflexifol has little toxicity and is effective in bolus and infusion schedules at doses equal to or greater than those feasible with 5FU and LV infused separately. A first-line phase II study in combination with oxaliplatin is planned. Clinical trial information: 044867.

A phase I study of pegylated doxorubicin (DOX) and weekly topotecan (TOP) in patients (pts) with advanced solid tumors

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 12018-12018
Author(s):  
G. A. Masters ◽  
M. Guarino ◽  
C. Schneider ◽  
D. Biggs ◽  
S. Grubbs
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Dose Level ◽  
Phase Ii ◽  
Phase I Study ◽  
Hematologic Toxicity ◽  
Advanced Solid Tumors ◽  
Level 1 ◽  
Grade 3 ◽  
Ecog Ps

12018 Background: The primary endpoint of this prospective phase I study of DOX-TOP in pts with advanced solid tumors was to identify the maximum tolerated dose and dose-limiting toxicities (DLT) of this combination. Other objectives included a description of additional toxicities and efficacy in this patient population with refractory cancers. Pharmacokinetic sampling of TOP plasma levels will be reported separately. Methods: Eligible pts had advanced solid tumors and had either failed standard chemotherapy (chemo) or were pts for whom no standard therapy existed. They had ECOG PS = 0–2, adequate organ function, and gave written, informed consent. Initial doses included DOX 40 mg/m2 day 1 and TOP 2 mg/m2 days 1, 8 and 15 q 28 days. TOP was to be escalated in cohorts of pts. DLT was defined as febrile neutropenia, grade 4 thrombocytopenia, any grade 3 non-hematologic toxicity, or the inability to receive subsequent treatment due to ongoing toxicity. Treatment was held for ANC < 1000 or platelets < 75,000. Results: Fourteen pts have been enrolled on this phase I study, all of whom were evaluable for toxicity. There were 12 males and 2 females, and the median age was 57 years (range 25–86). Four had ECOG PS = 0, 9 had PS = 1, and 1 had PS = 2. Cancer types included head and neck (3), renal (2), and breast, pancreas, liver, esophagus, germ cell tumor, sarcoma, and others (one each). In the 6 pts treated at dose level 1, toxicities included grade 3 anemia (1) and neutropenia (2), and grade 4 neutropenia (1). DLT consisted of grade 4 thrombocytopenia (1) and inability to deliver day 15 TOP in 3/6 pts at this dose. Thus, TOP was reduced to 1.5 mg/m2 weekly for dose level -1, and 8 pts have been treated. Toxicities included grade 3 anemia (1)and neutropenia (2), and grade 4 neutropenia (1) and thrombocytopenia (1). Enrollment continues at this dose level to confirm tolerability. No patient achieved an objective response to therapy, but 2 pts have stable disease for up to 4 cycles. Conclusions: DOX-TOP can be safely combined in pts with advanced solid tumors, with hematologic toxicity as the DLT. The preliminary recommended phase II dose is DOX 40 mg/m2 and TOP 1.5 mg/m2. We plan to explore an additional dose level of DOX 30 mg/m2 and TOP 2 mg/m2. Phase II evaluation is contemplated in selected tumor types. [Table: see text]

scholarly journals 295 First-in-human Phase I trial of IBI188, an anti-CD47 targeting monoclonal antibody, in patients with advanced solid tumors and lymphomas

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A322-A322
Author(s):  
Nehal Lakhani ◽  
Marlana Orloff ◽  
Siqing Fu ◽  
Ying Liu ◽  
Yan Wang ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
T Cells ◽  
Solid Tumors ◽  
Dose Level ◽  
Maintenance Dose ◽  
Receptor Occupancy ◽  
Priming Dose ◽  
Dose Escalation Study ◽  
Optimal Maintenance ◽  
Grade 3

BackgroundIBI188 is a humanized IgG4 monoclonal antibody targeting CD47, an antiphagocytic (‘don’t eat me’) signal present on cancer cells. Blockage of this myeloid checkpoint, IBI188 enhances tumor cell phagocytosis and cross priming of T-cells. We conducted a first-in-human phase 1a trial to evaluate the tolerability, safety and PK/PD characteristics of IBI188. (NCT03763149).MethodsPatients with advanced/refractory solid tumors or lymphoma were enrolled in this two-part dose-escalation study: Part A for testing optimal priming doses at 0.1, 0.3, and 1 mg/kg and Part B for optimal maintenance doses at 3, 10, 20, 30 mg/kg weekly. An accelerated titration followed by traditional 3+3 design was used in this study with a 28-day dose-limiting toxicity (DLT) observation period. Primary endpoint was safety profile; secondary endpoints included PK parameters and PD markers, i.e. CD47 receptor occupancy.ResultsAs of June 18, 2020, 20 patients have been enrolled, 6 in Part A and 14 in Part B. There was no DLT reported at any dose level. The median treatment duration was 1.8 months (0.2–5.5) months. The most common treatment-related adverse events (TRAEs) were nausea (n=7), back pain (n=7), fatigue (n=6), vomiting (n=4) and blood bilirubin increased (n=4). Three patients had ≥ Grade 3 TRAEs (Grade 3 blood bilirubin increase, Grade 4 platelet count decrease and Grade 3 anemia, each in 1 patient). Three of 20 patients (15%) had anemia, an expected TRAE associated with the mechanism of IBI188. Majority of the patients (65%) had infusion related reactions (IRR). All IRRs were Grade 1–2 and able to be managed with standard IRR treatment. The clearance of IBI188 decreased with the increasing dose from 3 to 20 mg/kg and IBI188 can overcome the sink at 10 mg/kg or higher dose level. The PK analysis at 30 mg/kg is ongoing. The 10 mg/kg maintenance dose resulted in T cells receptor occupancy above 80%. After multiple administrations (≥ 3 times, including the priming dose), the RBC and T cells receptor occupancy tends to be stable and maintained around 90%. The receptor occupancy analysis at 20 mg/kg and 30 mg/kg is ongoing.ConclusionsIBI188 was well tolerated at 1 mg/kg priming dose following by the maintenance dose up to 30 mg/kg.Trial RegistrationNCT03763149

Phase I clinical and pharmacologic study of weekly cisplatin combined with weekly irinotecan in patients with advanced solid tumors.

1998 ◽  
Vol 16 (12) ◽  
pp. 3858-3865 ◽  
Author(s):  
L B Saltz ◽  
D Spriggs ◽  
L J Schaaf ◽  
G K Schwartz ◽  
D Ilson ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Maximum Tolerated Dose ◽  
Clinical Activity ◽  
Weekly Schedule ◽  
Previously Treated Patients ◽  
Previously Treated ◽  
Irinotecan Dose ◽  
Pharmacologic Study

PURPOSE In vitro synergy between cisplatin and irinotecan (CPT-11) has been reported. We designed a combination schedule of these agents to maximize the potential for synergistic interaction. PATIENTS AND METHODS To maximize the opportunity for synergy, we divided the cisplatin into four consecutive weekly treatments, followed by a 2-week rest. Each dose of cisplatin was immediately followed by a dose of irinotecan. The dose of cisplatin was fixed at 30 mg/m2/wk. The initial irinotecan dose was 50 mg/m2/wk and this was escalated by 30% increments in successive cohorts of three to six patients to establish the maximum-tolerated dose (MTD). Pharmacokinetics of irinotecan and its metabolites, SN-38 and SN-38 glucuronide (SN-38G), were analyzed. RESULTS Of 35 patients with solid tumors enrolled onto this trial, 30 were assessable for toxicity and response. The MTD for this regimen was 30 mg/m2/wk of cisplatin plus 50 mg/m2/wk of irinotecan in previously treated patients and 30 mg/m2/wk of cisplatin plus 65 mg/m2/wk of irinotecan in chemotherapy-naive patients. Neutropenia was the dose-limiting toxicity (DLT) encountered in this trial. Diarrhea was infrequent and rarely dose-limiting. Seven of 30 assessable patients achieved a partial response. No alteration in irinotecan, SN-38, or SN-38G pharmacokinetics resulted from the administration of cisplatin with irinotecan. CONCLUSION The administration of cisplatin and irinotecan on this weekly schedule provides a practical and well-tolerated regimen that has the potential to maximize any clinical synergy between the two agents. Evidence of substantial clinical activity was seen in this phase I study.

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