A Phase I/II, Dose-Escalation Study of Daratumumab, A CD38 Mab in Patients with Multiple Myeloma – Preliminary Safety Data

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1873-1873 ◽  
Author(s):  
Peter Gimsing ◽  
Torben Plesner ◽  
Hareth Nahi ◽  
Henk Lokhorst ◽  
Marie-Louise Valentin ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Dose Escalation ◽  
Safety Profile ◽  
Treatment Options ◽  
Dose Range ◽  
Safety Data ◽  
Dose Escalation Study ◽  
Full Dose ◽  
Grade 3 ◽  
Trial Drug

Abstract Abstract 1873 Background: Patients with multiple myeloma (MM) relapsed or refractory to current treatment options and ineligible for ASCT have a poor prognosis. Therefore new treatment options are highly needed for this patient population. Malignant MM cells exhibit very strong CD38 surface expression. Daratumumab is a human CD38 antibody with broad spectrum killing activity. Daratumumab mediates MM cell death via antibody dependent cellular cytotoxicity, complement dependent cytotoxicity and apoptosis. Daratumumab has been shown to inhibit growth of CD38-expression tumor cells in SCID mouse xenografts. We report the preliminary safety results from the ongoing first in man dose-escalation study (clin.trial.gov. NCT00574288). Methods: Patients (age > 18 yrs) ineligible for ASCT and relapsed or refractory to at least two different prior therapies receive 7 full and 2 pre-dose infusions of daratumumab (1st pre-dose day 1, 1st full dose day 2, 2nd pre-dose day 21, 2nd full-dose day 22 and thereafter weekly full-dose daratumumab). The study design encompasses a classic 3 + 3 dose escalation with the possibility to limit exposure to 1 patient in the first 2 cohorts pending safety data. The dose range is from 0.005 mg/kg to 24 mg/kg. The primary objective is to establish the safety profile and secondary objectives are to establish MTD and evaluate the efficacy. An independent Data Monitoring Committee evaluates the safety data for each cohort before dose-escalation. Results: Until May 31st, 2011 safety data for 20 patients, including dose range from 0.005 mg/kg up to 2 mg/kg cohort, were collected. Median age 62 yrs (42–76), F/M: 7/13, stage of MM (ISS): 1: 5 patients; 2: 9 patients; 3: 5 patients and 1 unknown. The most common AEs reported across all cohorts are pyrexia (35%), free hemoglobin (25%), anemia (25%), proteinuria (25%), cough (15%), dizziness (10%), flushing (10%), influenza-like-illness (10%), nausea (10%) hypo/hypertension (10%/10%), thrombocytopenia (10%), hemolysis (15%), lymphopenia (10%), arthralgia (10%), abdominal pain (10%) and chest pain (10%). Five SAE were assessed as related to daratumumab. One patient had anemia grade 3 and thrombocytopenia grade 4, one patient experienced cytokine release syndrome grade 2 and based on these DLT events 3 more patients were enrolled in the 0.1 mg/kg and 1.0mg/kg cohorts, one patient experienced a grade 3 bronchospasm 40 hours after end of trial drug infusion and one patient had AST elevation. All patients recovered after relevant treatment. Since implementation of relevant pre-medication and dilution of trial drug no severe infusion related AEs have been reported. The MTD has not been reached at the cut-off time point for this evaluation. Efficacy evaluation is ongoing and preliminary data will be presented at the meeting. Conclusion: Daratumumab has a favorable safety profile as monotherapy in patients with multiple myeloma in doses up to and including 2 mg/kg. The dose-escalation is ongoing and updated safety data will be presented at the meeting. When the MTD is established, an extension study with daratumumab as monotherapy will be conducted. Disclosures: Plesner: Genmab A/S: Consultancy. Lokhorst:Genmab: Consultancy. Valentin:Genmab A/S: Employment. Lisby:Genmab A/S: Employment. Richardson:Genmab: Consultancy.

ARRY-520 Shows Durable Responses in Patients with Relapsed/Refractory Multiple Myeloma in a Phase 1 Dose-Escalation Study

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1860-1860 ◽  
Author(s):  
Jatin J Shah ◽  
Jeffrey Zonder ◽  
Adam Cohen ◽  
Robert Z. Orlowski ◽  
Raymond Alexanian ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Febrile Neutropenia ◽  
Dose Escalation ◽  
Safety Profile ◽  
Research Funding ◽  
Phase 1 ◽  
Phase 1 Study ◽  
Acceptable Safety Profile ◽  
Heavily Pretreated ◽  
Grade 3

Abstract Abstract 1860 Background: ARRY-520 is a potent, selective inhibitor of kinesin spindle protein (KSP, eg5) which is required for cell cycle progression through mitosis. Treatment with ARRY-520 arrests cells in mitosis with subsequent induction of apoptosis due to degradation of survival signals during mitotic arrest. Cancers, such as multiple myeloma (MM), that depend on the short-lived survival protein Myeloid cell leukemia (MCL)-1 are highly sensitive to treatment with ARRY-520 in preclinical MM models, providing a strong rationale for its clinical investigation in this disease. Methods: This Phase 1 study was designed to evaluate the safety, pharmacokinetics (PK), preliminary efficacy and biological activity of ARRY-520 administered intravenously on Days 1 and 2 every 2 weeks without/with granulocyte colony-stimulating factor (G-CSF) support. Eligible patients (pts) had relapsed or refractory MM with ≥ 2 prior lines of therapy (including both bortezomib [BTZ] and an immunomodulatory [IMiD] agent), unless refusing or ineligible for this therapy. Cohorts were enrolled in a classical 3+3 dose escalation design. Results: Enrollment in this Phase 1 study is complete. Thirty-one pts have been treated, with a median age of 60 years (range 43–79) and a median of 6 prior regimens (range 2–16). All pts received a prior proteasome inhibitor (30 pts BTZ, 4 pts carfilzomib) and an IMiD-based agent (28 pts lenalidomide, 23 pts thalidomide). Twenty-four pts had an autologous stem cell transplant. The maximum tolerated dose (MTD) was determined to be 1.25 mg/m2/day without G-CSF. As neutropenia was the dose-limiting toxicity (DLT), dose escalation with G-CSF support was conducted and the MTD for ARRY-520 with G-CSF was determined to be 1.5 mg/m2/day. At the MTD, 1 of 7 pts had a DLT of febrile neutropenia. At doses above the MTD, additional DLTs of Grade 3 mucositis and Grade 3 corneal disorder were observed. ARRY-520 demonstrated an acceptable safety profile. The most commonly reported treatment-related adverse events (AEs) included hematologic events (anemia, leukopenia, neutropenia, thrombocytopenia), as well as anorexia, blurred vision, diarrhea, dizziness, fatigue, febrile neutropenia, mucositis, nausea and rash. No treatment-related AEs of neuropathy or alopecia were reported at the MTD. ARRY-520 has been dosed over extended periods of time (to date, median 7 cycles [range 1–44]), with no evidence of cumulative toxicity. The plasma concentrations of ARRY-520 were determined over a 7-day period during Cycle 1 following the Day 1 and 2 infusions of ARRY-520. The preliminary noncompartmental PK parameter estimates in this population were similar to those observed in prior oncology studies. The PK was characterized by low clearance (CL = 2.2 L/hr/m2) and a large volume of distribution (Vss = 232 L/m2). The t1/2 of elimination was very long (67 hrs). Concentrations were typically maintained above the in vitro IC50 for KSP inhibition for ≥ 7 days suggesting therapeutically active concentrations of drug were maintained in pts for sustained periods. Further analyses of PK relative to safety and activity are on-going. ARRY-520 showed activity as a single agent across a range of doses in this heavily pretreated population (31 evaluable pts) with 3 confirmed partial responses (PR) and 1 confirmed minimal response (MR) per International Melanoma Working Group (IMWG) and European Group for Blood and Marrow Transplantation (EMBT) criteria. PRs had a median of 7 prior therapies (range 2–8). Responses were durable; to date, the durations of responses for PRs were 3.4+ months (mos), 11.9+ mos and 12.0 mos, respectively. Of interest, the time to response with ARRY-520 was prolonged, with a median time to PR of 3.7 mos (range 3.7–8.1). Notably, responses were observed in pts refractory to multiple standard-of-care agents. In addition, 4 pts experienced a best response of stable disease (SD) lasting ≥ 10 mos. To date, 5 pts remain on study, including 2 of 3 PRs. Conclusions: In this Phase 1 study, ARRY-520 shows promising evidence of clinical activity, with a long duration of response and an acceptable safety profile in heavily pretreated MM Patients. A Phase 2 portion of the study is ongoing to obtain additional information on the efficacy, safety and biological effects of ARRY-520 at 1.5 mg/m2/day with G-CSF support. Disclosures: Shah: Array BioPharma: Consultancy, Research Funding; Celgene: Consultancy; Onyx: Consultancy, Research Funding. Off Label Use: ARRY-520. Zonder:Millenium: Consultancy, Research Funding, Speakers Bureau; Celgene: Speakers Bureau; Medtronics: Honoraria; Amgen: Consultancy. Cohen:Celgene: Consultancy, Honoraria; Millenium: Consultancy, Honoraria; Onyx: Consultancy, Honoraria. Orlowski:Array BioPharma: Honoraria, Membership on an entity's Board of Directors or advisory committees. Alexanian:Array BioPharma: Research Funding. Thomas:Array BioPharma: Research Funding; Centecor: Research Funding; Novartis: Research Funding; Immunomedics: Research Funding; Celgene: Research Funding; Millenium: Research Funding. Weber:Array BioPharma: Research Funding. Kaufman:Keryx: Consultancy; Celgene: Research Funding; Merck: Research Funding. Walker:Array BioPharma: Employment, Equity Ownership. Litwiler:Array BioPharma: Employment. Karan:Array BioPharma: Employment. Hilder:a: Employment. Ptaszynski:Array BioPharma Inc.: Consultancy. Lonial:Millenium: Consultancy; Celgene: Consultancy; Novartis: Consultancy; Bristol Myers Squibb: Consultancy; Onyx: Consultancy; Merck: Consultancy.

Final results: A dose escalation phase I study of ARQ 197, a selective c-Met inhibitor, in patients with metastatic solid tumors

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 3548-3548 ◽  
Author(s):  
T. Mekhail ◽  
T. Rich ◽  
L. Rosen ◽  
F. Chai ◽  
Z. Semic-Suka ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Safety Profile ◽  
Safety Data ◽  
Dose Escalation Study ◽  
Tumor Cell Migration ◽  
Drug Concentrations ◽  
Arq 197 ◽  
Favorable Safety

3548 Background: ARQ 197 is a selective, non-ATP competitive inhibitor of c-Met, a receptor tyrosine kinase implicated in tumor cell migration, invasion, and proliferation. Methods: This phase I dose escalation study enrolled patients (pts) with metastatic solid tumors to determine the drug's safety profile, maximum tolerated dose (MTD), recommended phase 2 dose (RP2D), pharmacokinetics (PK), and preliminary antitumor activity. Dose escalation followed an accelerated titration design and was modified to the traditional escalation design (3+3 pts) once grade 2 toxicity was observed. ARQ 197 was initially administered orally twice daily (BID) for 2 weeks followed by 1 week off and then modified to evaluate continuous BID dosing based on favorable safety data. Intra-patient dose-escalation was allowed in this study. Additional pts were enrolled and treated at the 360 mg bid continuous dose, which was determined to be the RP2D in another phase I clinical trial. Results: To date, 65 pts (38 male/27 female; median age 61; 9 colon/colorectal, 8 renal cell carcinoma/kidney, 6 ovarian, 6 sarcoma, 5 lung cancer and 31 others) have been treated at 11 dose levels (10 mg bid to 360 mg bid). All treated pts achieved plasma drug concentrations significantly above in vitro IC50 values. The most common drug-related adverse events (AEs) were fatigue (18.5%) and nausea (12.3%). One case each of the following drug-related serious AEs were reported in 4 pts: anemia, leukopenia, neutropenia, thrombocytopenia, dehydration, liver failure, abdominal pain, nausea, and vomiting. Three pts with neuroendocrine, prostate, or testicular cancer achieved a partial response (PR), 32 demonstrated stable disease (SD) and 13 progressed. The 3 PR pts were initially treated at 10, 40 or 90 mg BID respectively. Their doses were escalated to 50, 70, or 120 mg BID respectively after 18 to 33 weeks on treatment. An overall response rate of 6.3% and a disease control rate (CR+PR+SD) of 72.9% were demonstrated among 48 pts who are evaluable for efficacy. Conclusions: ARQ 197 has demonstrated a favorable safety profile up to the dose of 360 mg bid. Preliminary evidence of anti-cancer activity was observed. Final study data on drug safety, PK and efficacy will be presented. [Table: see text]

Dose-escalation trial of milatuzumab (humanized anti-CD74 monoclonal antibody) in multiple myeloma

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 8593-8593 ◽  
Author(s):  
J. L. Kaufman ◽  
R. Niesvizky ◽  
E. A. Stadtmauer ◽  
A. Chanan-Khan ◽  
D. Siegel ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Dose Escalation ◽  
Serum Levels ◽  
Infusion Reaction ◽  
Cord Compression ◽  
Dose Escalation Study ◽  
Promising Target ◽  
Disease Stabilization ◽  
Heavily Pretreated ◽  
Grade 3

8593 Background: CD74 (HLA-DR-associated invariant chain) is highly expressed in multiple myeloma (MM), rapidly internalized, and a promising target for immunotherapy. Methods: A multicenter dose-escalation study was initiated in patients (pts) with relapsed/refractory MM who had failed at least 2 standard therapies. Pts received milatuzumab IV twice-weekly for 4 wks, with doses escalated by a 3+3 cohort design. Pts were evaluated over 12 wks, with responding pts continuing follow-up. AEs and safety laboratories were evaluated by NCI CTC v3 grades, with any treatment-related Grade 3–4 events considered dose-limiting toxicity (DLT). Responses were classified by EBMT criteria, with PK and immunogenicity evaluated by serum milatuzumab levels and human anti-milatuzumab antibody (HAHA) titers, respectively. Results: Twenty-one pts (12M/9F, median age 63) have now received 1.5 (n=8), 4.0 (n=9) or 8.0 mg/kg (n=4) doses twice weekly. They had MM for 0.9–16.8 years (median 5.4), predominantly IgG subtype, were heavily pretreated (4 median prior treatments), and were Durie-Salmon stage II (n=13) or III (n=8). After increasing premedications and slowing administration, infusions were well tolerated (Grade 1–2). There was 1 DLT (infusion reaction) and 3 SAEs (bact. meningitis, confusion/hypercalcemia, fever post demerol) at 1.5 mg/kg, 1 DLT (unexplained anemia) and 2 SAEs (cord compression, epistaxis/thrombocytopenia), at 4.0 mg/kg, but no DLTs or SAEs at 8.0 mg/kg. There has been no pattern of other AEs nor effects on routine laboratories, including serum chemistries, CBC, serum immunoglobulins, B- or T-cells, and no cases of HAHA. At current doses, milatuzumab is rapidly cleared from serum, with little accumulation and low trough levels across infusions. There have been no objective responses so far, but 4 pts have had stable disease by EBMT criteria for at least 3 months post-treatment, occurring with a possible trend towards higher milatuzumab serum levels than pts with earlier disease progression. Conclusions: Milatuzumab doses up to 8.0 mg/kg may be given safely twice-weekly for 4 weeks. In spite of rapid clearance, several patients have had disease stabilization at 4.0 and 8.0 mg/kg doses, which is encouraging. Accrual of the next cohort receiving 16.0 mg/kg is ongoing. [Table: see text]

scholarly journals Dose escalation study of targeted alpha therapy with [225Ac]Ac-DOTA-substance P in recurrence glioblastoma – safety and efficacy

2021 ◽  
Author(s):  
Leszek Królicki ◽  
Frank Bruchertseifer ◽  
Jolanta Kunikowska ◽  
Henryk Koziara ◽  
Dariusz Pawlak ◽  
...  
Keyword(s):  
Adverse Effects ◽  
Dose Escalation ◽  
Liver Toxicity ◽  
Performance Status ◽  
Treatment Options ◽  
Recurrent Glioblastoma ◽  
Mri Imaging ◽  
Dose Escalation Study ◽  
Good Tolerability ◽  
Grade 3

Abstract Glioblastoma is the most common and malignant primary brain tumour, with a poor prognosis. Introduction of new treatment options is critically important. The study aimed to assess the appropriateness of escalation doses and toxicity of [225Ac]Ac-DOTA-SP therapy. Material and methods A total of 21 patients (age of 43.0 ± 9.5 years), with histologically confirmed recurrent or conversion glioblastoma grade 4 following a standard therapy, have been included in the study. One to 2 intracavitary port-a-cath systems were stereotactically inserted. Patients were treated with escalation dose protocol with 10, 20 and 30 MBq per cycle totally 1–6 doses of [225Ac]Ac-DOTA-SP in 2-month intervals. Therapeutic response was monitored by clinical performance status and MRI imaging. Results Treatment was well tolerated with mostly mild temporary adverse effects (oedema, epileptic seizures, aphasia, hemiparesis) mainly in the group of patients treated with 30 MBq of [225Ac]Ac-DOTA-SP. Only one patient treated with 30 MBq revealed thrombopenia grade 3. There was no other grade 3 and 4 toxicity related to [225Ac]Ac-DOTA-treatment in all groups. The median overall survival time from the primary diagnosis (OS-d) was 35.0 months and from the diagnosis of the recurrence/conversion (OS-r/c) was 13.2 months. From the start of treatment with [225Ac]Ac-DOTA-SP, the median PFS was 2.4 months, and the OS-t was 9.0 months. There were no statistically significant differences between the investigated dose escalation groups. Conclusions Treatment of recurrent glioblastoma with [225Ac]Ac-DOTA-SP is safe and well tolerated up to 30 MBq per cycle. The escalation dose protocol showed good tolerability. Only mild temporary adverse effects were observed. No remarkable haematological, kidney and liver toxicity was seen.

Phase I Study of Lorvotuzumab Mertansine (LM, IMGN901) in Combination with Lenalidomide (Len) and Dexamethasone (Dex) in Patients with CD56-Positive Relapsed or Relapsed/Refractory Multiple Myeloma (MM)

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 728-728 ◽  
Author(s):  
Jesus G. Berdeja ◽  
Francisco Hernandez-Ilizaliturri ◽  
Asher Chanan-Khan ◽  
Manish Patel ◽  
Kevin R. Kelly ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Phase I ◽  
Dose Escalation ◽  
Safety Profile ◽  
Phase I Study ◽  
Complete Response ◽  
Clinical Activity ◽  
Safety And Efficacy ◽  
Grade 3 ◽  
Expansion Cohort

Abstract Abstract 728 Background: LM, an antibody-drug conjugate (ADC), is designed to specifically kill CD56+ cancer cells and contains a potent maytansinoid cytotoxic agent (DM1) attached to a CD56-targeting antibody. MM shows CD56 expression in >70% of cases. LM has demonstrated single agent clinical activity and an acceptable safety profile in relapsed/refractory (rel/ref) MM patients. Preclinical studies showed enhanced anti-MM activity when LM was combined with Len/Dex. To further study the safety and efficacy of LM in combination with Len/Dex, a phase I study was conducted in rel/ref patients. This abstract reports updated results on the safety and efficacy of LM/Len/Dex and preliminary results on the pharmacokinetics (PK) and immunogenicity studies. Methods: Primary study objectives were to determine the safety, maximum tolerated dose (MTD), recommended phase 2 dose (RP2D), anti-MM activity and PK of LM in combination with standard oral (PO) doses of Len (25 mg po, daily on days 1–21) and Dex (40 mg po on D 1, 8, 15, and 22) in CD56+ rel/ref MM patients who have received at least 1 prior therapy. LM was given intravenously (IV) on D 1, 8, and 15 on a 28-day cycle. Dose escalation was conducted in new cohorts of patients to define the MTD, which was then further evaluated in a dose-expansion cohort. Adverse events (AEs) were assessed using CTCAEv3 criteria, and dose-limiting toxicity (DLT) determination was based on the occurrence of AEs that were probably or definitely attributed to the study regimen. Efficacy was assessed using the International Myeloma Working Group (IMWG) criteria. Enrollment has completed and 16 patients remain on study. Results: Forty-four patients were enrolled, 41 are currently evaluable for safety and 32 are evaluable for efficacy. The median number of prior therapies was 2 (range 1–11), 62% of patients had prior Len exposure and 33% were Len refractory. LM doses of 75 (N = 11), 90 (N=4), and 112 (N =6) mg/m2 were evaluated in the dose-escalation phase. The most common AE was peripheral neuropathy (PN), which occurred more frequently at higher LM doses (55% at 75 mg/m2 and 100% at 90 and 112 mg/m2); Grade 3 PN was seen only in patients treated at 90 mg/m2 or above. PN emerged, in most cases, in cycles >3 and was manageable with LM dose modification. During dose escalation, 1 patient experienced Grade 4 neutropenia and hyperuricemia. The 75 mg/m2 LM dose was considered the MTD based on overall tolerability and the lower incidence of PN observed, and was further tested to determine its suitability as the RP2D in the dose expansion portion of the study (N=23 patients, 19 patients available for safety evaluation). Grade 1–2 PN occurred in 8 patients (42%) and grade 3 PN was observed only in 1 pt in the dose-expansion cohort. Two patients developed grade 3 tumor lysis syndrome (TLS). Other grade 3 AEs reported in 1 patient each (5%) in the dose-expansion cohort consisted of neutropenia, thrombocytopenia, anemia, hemolytic anemia, and LDH increase. Efficacy was observed across all dose levels and the overall response rate (ORR) was 59%, including 1 patient each with stringent complete response (sCR) and complete response (CR), 8 patients with very good partial remission (VGPR), and 9 patients with partial remission (PR). No immunogenicity against the antibody (HAHA) or DM1 component (HADA) of LM was detected. PK results from 18 patients treated at 75 mg/m2 indicate LM Cmax and exposure in this combination regimen is consistent with LM monotherapy. Conclusions: Based on all available safety data, 75 mg/m2 was considered the RP2D. LM at 75mg/m2 in combination with Len and Dex has shown objective evidence of clinical activity with an acceptable safety profile. Disclosures: Off Label Use: Lorvotusumab mertansine is not FDA approved for treatment of multiple myeloma alone or in combination with lenalidomide and dexamethasone as is investigated in this trial. Running:ImmunoGen, Inc.: Employment. Murphy:ImmunoGen, Inc.: Employment. Guild:ImmunoGen, Inc.: Employment. Carrigan:ImmunoGen, Inc: Employment. Ladd:ImmunoGen, Inc.: Employment. Wolf:ImmunoGen, Inc.: Employment, Equity Ownership. O'Leary:ImmunoGen, Inc.: Employment. Ailawadhi:Millenium Pharmaceuticals: Speakers Bureau.

Phase I dose-escalation study of XL147, a PI3K inhibitor administered orally to patients with solid tumors

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 3500-3500 ◽  
Author(s):  
G. Shapiro ◽  
E. Kwak ◽  
J. Baselga ◽  
J. Rodon ◽  
C. Scheffold ◽  
...  
Keyword(s):  
Steady State ◽  
Solid Tumors ◽  
Skin Rash ◽  
Dose Escalation ◽  
Plasma Concentrations ◽  
Safety Data ◽  
Pi3k Pathway ◽  
Dependent Manner ◽  
Dose Escalation Study ◽  
Grade 3

3500 Background: XL147 is a selective inhibitor of Class I PI3K isoforms. In preclinical cancer models XL147 is cytostatic or cytoreductive as monotherapy and enhances the efficacy of targeted agents and chemotherapeutics. This open label, Phase 1 dose escalation study assesses the safety, pharmacokinetics, pharmacodynamics, and efficacy of XL147 in advanced solid tumors. Methods: For each 28 day cycle, patients (pts) receive XL147 on Days 1–21 (21/7) or as a continuous daily dose (CDD). Cycle 1 safety data determine dose-limiting toxicities (DLTs). Tumor response is assessed every 8 weeks. Results: As of December 2008, 39 pts have been treated: 36 on 21/7 across 7 dose levels (30–900 mg) and 3 on CDD at 100 mg. At 900 mg, 2 of 3 pts experienced a DLT of reversible grade 3 rash, and the MTD was established as 600 mg based on 15 pts. Drug-related toxicities included grade 3 skin rash (3 pts), grade 3 arterial thrombosis (1 pt), grade 2 transaminase elevation (1 pt), and grade 1 hyperglycemia (4 pts). XL147 exposure increased with dose from 30–400 mg and was similar from 400–900 mg. XL147 reached steady-state plasma concentrations by Day 15–20. Mean t1/2, z at steady-state ranged from 3.7–6.3 days. Doses ≥400 mg yielded exposures that exceeded the EC90 in xenograft models. A trend suggesting augmented food-induced changes in insulin was evident; however, glucose was minimally affected. XL147 reduced levels of phosphorylated PI3K pathway components in PBMCs, hair, skin, and tumor tissues in an exposure-dependent manner. In 2 pts dosed at the MTD, reductions of ≥70% in PI3K pathway signaling were observed in tumor tissue without compensatory upregulation of MEK/ERK phosphorylation. As of December 2008, 6 pts (3 NSCLC, 1 BCC, 1 NHL, 1 PC) continued on study >6 months including 3 >10 months (NHL, NSCLC, BCC). One pt with hormone refractory PC has sustained a normalization of PSA levels through 5 months. Conclusions: XL147 was generally well tolerated with the MTD for the 21/7 schedule defined as 600 mg. The most common drug-related toxicity was skin rash. Inhibition of PI3K pathway signaling has been demonstrated in tumor and surrogate tissues. Prolonged stable disease has been observed. [Table: see text]

A phase I open-label, dose-escalation study of intravenous ascorbic acid in combination with gemcitabine and erlotinib in patients with metastatic pancreatic cancer.

2012 ◽  
Vol 30 (4_suppl) ◽  
pp. 323-323 ◽  
Author(s):  
Susan Joy Littman ◽  
Daniel Monti ◽  
Andrew Newberg ◽  
Anthony Bazzan ◽  
Madhavan V. Pillai ◽  
...  
Keyword(s):  
Ascorbic Acid ◽  
Steady State ◽  
Phase I ◽  
Dose Escalation ◽  
Safety Data ◽  
Open Label ◽  
Dose Escalation Study ◽  
First Line Therapy ◽  
Grade 3 ◽  
Vit C

323 Background: IV ascorbic acid (vit c) is a prodrug for steady state formation of ascorbate radical (Asc·-) in the extracellular space resulting in sustained production of H2O2 leading to selective killing of tumor cells by a pro-oxidative mechanism. In preclinical models of panc cancer pharmacologic concentrations of Asc·- with gem resulted in a synergistic cytotoxic response. We conducted a Phase I dose escalation study of IV ascorbic acid with gem plus erlotinib chemo as first line therapy in panc cancer. Methods: Patients with adv panc cancer were enrolled using a standard 3+3+3 design to assess the safety and pharmacology of IV vit c in combo with gem and erlotinib. Cohort 1 received 50 g IV vit c and subsequent cohorts were escalated by 25 g to a final dose of 100 g. Pts were given 3 infusions of vit c per week on separate days for 8 w (1 cycle). IV gem was given on day 1 (1000 mg/m2) and weekly for 7 w followed by a rest week. Oral erlotinib (100 mg) was given daily for 8 w. Trt continued until disease progression or toxicity. Steady state ascorbate PK was assessed in cohorts 2 and 3. AEs were determined using NCI CTCAE v3.0. Tumor responses were assessed per RECIST. Results: Of 14 pts enrolled, 9 or 3 per cohort completed the study. Median age was 64 years. 5 pts did not complete trt (2 discontinued, 3 died). 9 pts completed at least 24 ascorbic acid trts and 1 cycle of gem/erlotinib therapy. There were 24 AEs. These included 15 non-serious AEs and 8 SAEs. The most frequent AEs were grade 1/2 thrombocytopenia. Other grade 1/2 events included anemia, hyperglycemia, abd discomfort, ascites and infection. SAEs: 2 grade 3 heme, 1 grade 3 GI, 1 grade 3 infectious and 2 grade 4 thrombosis. Plasma asc levels were 25.3 - 31.9 mm/L for pts receiving the 100g dose. 8 of the 9 pts had a reduction in the panc primary with 1 pt having no change at 8 w. For non-target lesions, 2 had PD and 7 had SD per RECIST. Conclusions: Overall safety data do not reveal AEs other than those expected in patients with metastatic panc cancer and/or treatment with gem and erlotinib. Addition of IV ascorbic acid did not increase toxicity. Preliminary efficacy results are encouraging. A phase II study is planned.

A phase I study of a novel IAP inhibitor APG-1387 as a monotherapy or in combination with pembrolizumab in treatments of patients with advanced solid tumors.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 3125-3125 ◽  
Author(s):  
Drew W. Rasco ◽  
Yufeng Li ◽  
Yuefen Tang ◽  
Lichuang Men ◽  
Hengbang Wang ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Dose Escalation ◽  
Dose Range ◽  
Advanced Solid Tumors ◽  
Antitumor Activities ◽  
Dose Escalation Study ◽  
Cancer Models ◽  
Elevated Bilirubin ◽  
Grade 3 ◽  
Apoptosis Proteins

3125 Background: APG-1387 is a novel, bivalent small molecule IAP (inhibitor of apoptosis proteins) inhibitor. It has shown strong antitumor activities in multiple human xenograft cancer models. APG-1387 also acts as host immune modulator, supporting the notion that APG-1387 in combination with anti-PD1 antibody for cancer therapy. Methods: This study consists of two parts (NCT03386526). Part 1 is the dose escalation study of APG-1387 including a mPC (metastatic pancreatic cancer) cohort expansion. Part 2 is the dose escalation and cohort expansion study of APG-1387 in combination with pembrolizumab. APG-1387 is administrated IV for 30 minutes once weekly in a 21-day-cycle. Pembrolizumab is administrated at 200mg IV on day1 of a 21-day-cycle. The study objectives are to assess the safety, pharmacokinetics (PK), pharmacodynamics (PD), and efficacy (assessed per RECIST v1.1 every 6 weeks). Results: Through Jan 4, 2019, total 23 patients had been treated in 4 cohorts of APG-1387 (20mg, 30mg, 45mg, 60mg). Two DLTs were observed at 60mg including lipase increase and Bell’s palsy, MTD was determined as 45mg. Nineteen of 23 patients experienced at least 1 TEAE. The most common TEAEs were nausea (21.7%), fatigue (17.4%), decreased appetite (13.0%), and abdominal pain (13.0%). Three grade 3 TEAEs including elevated bilirubin, lipase increase, and shortness of breath were documented at 45mg and 60mg. Three out of six mPC patients (one at 60mg, two at 45mg) achieved SD, one of them at 45mg has been treated > 5 cycles with confirmed SD (-18%). Two patients, who were treated with APG-1387 at 20mg in combination with pembrolizumab, had no DLT observed during the first cycle. Preliminary PK data of APG-1387 showed a dose proportionality in exposure (Cmax and AUC) over the dose range of 20-60 mg. Conclusions: APG-1387 was well tolerated and had manageable adverse events. The potential effects of APG-1387 alone or in combination with pembrolizumab deserve further exploration in patients with advanced solid tumors, especially in the mPC patients. Clinical trial information: NCT03386526.

scholarly journals Nivolumab Plus Ipilimumab in Patients With Advanced Melanoma: Updated Survival, Response, and Safety Data in a Phase I Dose-Escalation Study

2018 ◽  
Vol 36 (4) ◽  
pp. 391-398 ◽  
Author(s):  
Margaret K. Callahan ◽  
Harriet Kluger ◽  
Michael A. Postow ◽  
Neil H. Segal ◽  
Alexander Lesokhin ◽  
...  
Keyword(s):  
Adverse Events ◽  
Phase I ◽  
Dose Escalation ◽  
Objective Response ◽  
Safety Data ◽  
Advanced Melanoma ◽  
Clinical Activity ◽  
Dose Escalation Study ◽  
Grade 3

Purpose The clinical activity observed in a phase I dose-escalation study of concurrent therapy with nivolumab (NIVO) and ipilimumab (IPI) in patients with previously treated or untreated advanced melanoma led to subsequent clinical development, including randomized trials. Here, we report long-term follow-up data from study CA209-004, including 3-year overall survival (OS). Patients and Methods Concurrent cohorts 1, 2, 2a, and 3 received escalating doses of NIVO plus IPI once every 3 weeks for four doses, followed by NIVO once every 3 weeks for four doses, then NIVO plus IPI once every 12 weeks for eight doses. An expansion cohort (cohort 8) received concurrent NIVO 1 mg/kg plus IPI 3 mg/kg once every 3 weeks for four doses, followed by NIVO 3 mg/kg once every 2 weeks, which is the dose and schedule used in phase II and III studies and now approved for patients with unresectable or metastatic melanoma. Results Among all concurrent cohorts (N = 94) at a follow-up of 30.3 to 55.0 months, the 3-year OS rate was 63% and median OS had not been reached. Objective response rate by modified WHO criteria was 42%, and median duration of response was 22.3 months. Incidence of grade 3 and 4 treatment-related adverse events was 59%. The most common grade 3 and 4 treatment-related adverse events were increases in lipase (15%), alanine aminotransferase (12%), and aspartate aminotransferase (11%). One treatment-related death (1.1%) occurred in a patient who had multiorgan failure 70 days after the last dose of NIVO plus IPI. Conclusion This is the longest follow-up for NIVO plus IPI combination therapy in patients with advanced melanoma. The 3-year OS rate of 63% is the highest observed for this patient population and provides additional evidence for the durable clinical activity of immune checkpoint inhibitors in the treatment of advanced melanoma.

scholarly journals A Phase I Dose Escalation Study of PT-112 in Patients with Relapsed or Refractory Multiple Myeloma

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 9-10
Author(s):  
Taxiarchis Kourelis ◽  
Sikander Ailawadhi ◽  
Dan T. Vogl ◽  
Dennis Cooper ◽  
Tyler D Ames ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Phase I ◽  
Dose Escalation ◽  
Research Funding ◽  
Single Agent ◽  
Private Company ◽  
Dose Escalation Study ◽  
Refractory Multiple Myeloma ◽  
Car T ◽  
Grade 3

Background: PT-112 is a novel pyrophosphate-platinum conjugate with a multi-modal mechanism of action that induces immunogenic cell death and is not susceptible to DNA-repair drug resistance pathways. In phase I studies in solid tumors, PT-112 demonstrated safety and efficacy as single agent and in combination with PD-L1 checkpoint inhibitor avelumab, crossing a range of dose levels (DL) and tumor types, including in heavily pre-treated patients (pts) non-responsive to immunotherapy and refractory to other modalities. Non-clinical, in vivo research using advanced imaging technology demonstrated that PT-112 reached the highest concentrations in bone tissue (osteotropism). Moreover, PT-112 was highly active in the orthotopic, immune-competent Vk*MYC mouse model of multiple myeloma, including drug-resistant transplant variants. Thus, a rationale for PT-112 as an investigational candidate in multiple myeloma was established. Here, we present results of a phase I dose escalation study of PT-112 in pts with relapsed or refractory multiple myeloma (RRMM). Methods: A 3+3 design was used to determine the recommended phase 2 dose (RP2D) for PT-112 (28-day cycle IV days 1, 8, 15) in pts with evaluable RRMM who had exhausted available therapies (Tx), with adequate bone marrow (abs neutrophil count ≥ 1.0 x 109/L; platelet count ≥ 50 x 109/L; and hemoglobin ≥ 8.0 g/dL) and renal function (calculated creatinine clearance ≥ 30 mL/min), and ECOG PS 0-2. Results: A total of 24 pts were treated with PT-112 monotherapy across 6 DLs: 125 mg/m2, 3 pts; 180 mg/m2, 4 pts; 250 mg/m2, 5 pts; 300 mg/m2, 4 pts; 360 mg/m2, 4 pts; 420 mg/m2, 4 pts. Patients had a median age of 72 years and were heavily pre-treated, with a median of 8 prior lines of systemic Tx: 22 (92%) pts were triple-class refractory with 19 (79%) pts penta-refractory, and 3 (13%) pts refractory to BCMA-based therapies. The most common treatment-related adverse events (TRAEs) were thrombocytopenia (58%), neutropenia (42%), diarrhea (38%), and nausea (38%). 38% of pts had ≥1 grade 3 non-hematologic TRAE, with no grade 4 non-hematologic TRAEs reported. One dose-limiting toxicity (DLT) of grade 4 neutropenia occurred at the 420 mg/m2 DL. In addition, due to frequent dose reductions and modifications at this DL, the safety committee declared 360 mg/m2 as the RP2D. Among 8 patients who received a starting dose at / above the RP2D, 2 had stable disease and 4 experienced responses to PT-112 Tx. These included a confirmed partial response (PR) achieved in a 79-year-old pt with kappa free light chain (FLC) disease treated at 360 mg/m2, whose previous Tx included combination regimens with most approved therapies (penta-refractory) and stem cell transplantation. FLC levels declined by 65% from baseline on PT-112 therapy and the pt remained progression free for 4.5 months. A 72-year-old pt treated at the 420 mg/m2 DL, reduced to 250mg/m2 every other week over the course of Tx due to grade 3-4 cytopenias, had a confirmed minor response. Prior Tx with multiple lines given over 9 years included stem cell transplantation, most approved therapies (penta-refractory), prior investigational antibody and CAR-T cell Tx (primary refractory to CAR-T). The patient was M-protein negative, kappa FLC levels declined by 32% following the first dose reduction, and the pt remained progression free and clinically stable without complaints for 4.5 months. Additionally, two transient, unconfirmed PRs occurred in patients at the 420mg/m2 DL: in a triple-class-refractory 82-year-old previously treated with 5 lines of Tx, with 70% reduction in kappa FLC during cycle 1; and in a penta-refractory 85-year-old, who experienced disappearance of M-protein during cycle 1 and Gr 4 neutropenia (DLT). Conclusions: PT-112 monotherapy was feasible and well tolerated in this heavily pre-treated, multi-refractory multiple myeloma population, and the Phase I clinical data appear to validate the developmental hypothesis, built upon activity in the Vk*MYC mouse model of multiple myeloma. Responses were confirmed in 25% of patients treated at / above the RP2D using single-agent PT-112, an encouraging result in a dose escalation trial conducted in heavily refractory patients. Activity of PT-112 in RRMM patients may be explained by its osteotropism and its unique mechanism of action compared to other drug classes used to treat this disease. Further clinical study of PT-112 in RRMM is warranted in a phase 2 clinical trial. Disclosures Ailawadhi: Celgene: Honoraria; Janssen: Research Funding; Pharmacyclics: Research Funding; Amgen: Research Funding; Medimmune: Research Funding; BMS: Research Funding; Cellectar: Research Funding; Phosplatin: Research Funding; Takeda: Honoraria. Vogl:Janssen: Consultancy; Celgene: Consultancy; MorphoSys: Consultancy; Takeda: Consultancy; Active Biotech: Consultancy, Research Funding; Oncopeptides: Consultancy; Karyopharm: Consultancy. Ames:Phosplatin Therapeutics: Current Employment, Current equity holder in private company. Yim:Phosplatin Therapeutics: Current Employment, Current equity holder in private company. Price:Phosplatin Therapeutics: Current Employment, Current equity holder in private company. Jimeno:Phosplatin Therapeutics: Current Employment, Current equity holder in private company.

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