Phase 1 dose-escalation study of the antiplacental growth factor monoclonal antibody RO5323441 combined with bevacizumab in patients with recurrent glioblastoma

Abstract Background: CP-751,871, a fully human IgG2 subtype monoclonal antibody, is a potent and specific inhibitor of the insulin- like growth factor type I receptor (IGF-IR). The IGF-IR regulates the growth, survival, adhesion and invasiveness of multiple myeloma cells. High IGF-IR expression is observed in poor-prognostic subtypes of multiple myeloma and its inhibition has been long proposed as a potential therapeutic approach for treatment of this disease. Methods: A phase 1 dose escalation study was conducted to define the safety and tolerability, and to characterize the pharmacokinetic and pharmacodynamic (granulocyte surface IGF-IR expression and serum IGF-I levels) properties of CP-751,871 in patients with multiple myeloma. Patient’s eligibility included previously treated multiple myeloma in relapse or refractory phase including those less than complete remission to autologous stem cell transplant or tandem transplant. Results: Following informed consent and screening, 47 patients were enrolled into 11 dose-escalation cohorts of CP-751,871 at doses from 0.025 to 20 mg/Kg. Median patient age was 60 years. Median number of previous regimens was 4 (range 1–8). CP-751,871 was given as an IV infusion on Day 1 of 4-week cycles. Patients with a suboptimal response to CP-751,871 alone were eligible to receive CP-751,871 in combination with either oral dexamethasone and/or rapamycin at the discretion of the investigator. Twenty-seven patients received CP-751, 871 in combination with dexamethasone, while four patients received rapamycin in combination with either CP-751,871 or CP-751,871 and dexamethasone. Median number of treatment cycles was 3 (range 1–16). Ten patients were dosed at the highest cohort of 20 mg/Kg. No CP-751,871 related dose limiting toxicities were identified. Grade 3 toxicities were all observed at the 20 mg/Kg cohort (1 hyperglycemia, 1 anemia, 1 AST increase, 1 accidental fall, 1 muscle weakness). Plasma CP-751,871 exposure increased with dose, and the pharmacokinetic characteristics were consistent with target-mediated disposition. Granulocyte IGF-IR expression was maximally down-regulated for the entire duration of the dosing period at doses ≥1.5 mg/kg, indicating a saturation of circulating targets. CP-751,871 also led to a dose-dependent increase in circulating IGF-I concentrations. Tumor response was assessed according to Blade criteria. Two remissions and 4 partial remissions were reported in patients treated with different doses of CP-751,871 in combination with dexamethasone. Interestingly, the 2 patients with remission were previously found to be refractory to dexamethasone treatment. Conclusions: These data indicate that CP-751,871 is well tolerated either as a single agent or in combination with dexamethasone. Furthermore, CP-751,981 in combination with dexamethasone, may constitute a novel and effective therapeutic approach for patients with multiple myeloma.

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Phase 1 first-in-human dose escalation study of cp-751,871, a specific monoclonal antibody against the insulin like growth factor 1 receptor

Journal of Clinical Oncology ◽

10.1200/jco.2006.24.18_suppl.7609 ◽

2006 ◽

Vol 24 (18_suppl) ◽

pp. 7609-7609 ◽

Cited By ~ 3

Author(s):

M. Lacy ◽

M. Alsina ◽

C. L. Melvin ◽

L. Roberts ◽

D. Yin ◽

...

Keyword(s):

Multiple Myeloma ◽

Monoclonal Antibody ◽

Growth Factor ◽

Dose Escalation ◽

Phase 1 ◽

Human Monoclonal Antibody ◽

Cell Transplant ◽

Insulin Like Growth Factor ◽

Dose Escalation Study ◽

Human Dose

7609 Background: Multiple lines of evidence indicate that the Insulin Like Growth Factor 1 Receptor (IGF-1R) plays a key role in the progression of multiple myeloma (MM). IGF-1 is a growth factor for MM cells. It promotes survival to the cytotoxic effects of chemotherapy in animal models of MM and its blood levels has been shown to correlate with those of paraprotein in MM patients. CP-751,871, a fully human monoclonal antibody, is a highly specific and potent inhibitor of the autophosphorylation of IGF-1R. Methods: Based on its mechanism of action and the potential relevance of IGF-1R in MM, a Phase 1 First-in-Human dose escalation study was initiated with the objective to define the safety and tolerability, and to characterize the pharmacokinetic and pharmacodynamic properties of CP-751,871 in this patient population. Patient’s eligibility included previously treated multiple myeloma in relapse or refractory phase and/or less than complete remission following autologous stem cell transplant or tandem transplant. Results: Following informed consent and screening, 10 dose-escalation cohorts of patients received from 0.025 to 10 mg/kg of CP-751,871 by iv infusion on Day 1 of 4-week cycles. In patients with a suboptimal response to CP-751,871 alone, oral dexamethasone was added to the treatment regimen. Patients received up to 14 cycles of CP-751,871 therapy, alone or in combination with dexamethasone. No dose limiting toxicities have been identified to date. Plasma CP-751,871 exposure increases with dose, and the pharmacokinetic characteristics are consistent with target-mediated disposition. Pharmacodynamic measurements indicate complete target saturation by CP-751,871 for the complete length of the dosing period. One near CR and 2 PR in combination with dexamethasone have been reported. Conclusions: These data indicate that CP-751,871 is well tolerated and may constitute a therapeutic approach for patients with multiple myeloma. [Table: see text]

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Phase I open-label, dose escalation of YH003, an anti-CD40 monoclonal antibody in combination with toripalimab (anti-PD-1 mAb) in patients with advanced solid tumors.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.2580 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 2580-2580

Author(s):

Jermaine Coward ◽

Afaf Abed ◽

Adnan Nagrial ◽

Ben Markman

Keyword(s):

Monoclonal Antibody ◽

Solid Tumors ◽

Dose Escalation ◽

Phase 1 ◽

Advanced Solid Tumors ◽

Open Label ◽

Dose Escalation Study ◽

Label Dose ◽

Febrile Episodes ◽

Antigen Presenting

2580 Background: YH003, a recombinant, humanized agonistic anti-CD40 IgG2 monoclonal antibody (mAb) specifically recognizes and agonizes CD40 on the antigen-presenting cells to enhance immune responses. Preclinical data have shown potent anti-cancer activity when combined with anti-PD-1 antibodies. Methods: This is an ongoing phase 1 dose-escalation study. Patients with advanced solid tumors receive YH003 by IV administration Q3W as monotherapy at 0.03 to 3.0 mg/kg for the first cycle (21 days) then in combination with Toripalimab at 240 mg Q3W for the 4 subsequent cycles in an accelerated “3+3” design. The safety, tolerability and preliminary efficacy data will be analyzed. Results: As of 31 Dec 2020 data cutoff, 9 patients (pts) were enrolled and treated at 0.03 mg/kg (n = 3), 0.1mg/kg (n = 3), and 0.3mg/kg (n = 3). The median age was 63 years (range 33-68). Baseline ECOG scores were 0 (7 pts) and 1 (2 pts) with a median of 2 prior lines therapy (range 1-7). 5 pts had received prior immunotherapy (PD-1/PD-L1 or PD-1+CTLA-4). As of data cutoff, no dose limiting toxicities (DLT) were observed. No Serious Adverse Event (SAE) or AEs leading to treatment discontinuation were reported. Four drug related AEs were reported including one Grade 1 (G1) choroidal thickening (related to YH003) at 0.03 mg/kg, one G1 fatigue (related to YH003) at 0.1 mg/kg, two G1 febrile episodes (one related to YH003 and the other related to combination treatment) at 0.3 mg/kg. Among 5 patients assessable for response, there were 2 SD (one with anti-PDL1 refractory Merkel cell carcinoma at 0.03 mg/kg and one with anti-PD1 refractory NSCLC at 0.1 mg/kg) and 1 PR with anti-PD1/anti-CTLA4 refractory ocular melanoma at 0.1 mg/kg. Conclusions: YH003 was well tolerated up to 0.3 mg/kg dose levels when combined with Toripalimab and has shown encouraging antitumor activity in patients with advanced solid tumors. Clinical trial information: NCT04481009.

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Safety, tolerability, and pharmacokinetics of TAK-701, a humanized anti-hepatocyte growth factor (HGF) monoclonal antibody, in patients with advanced nonhematologic malignancies: First-in-human phase I dose-escalation study.

Journal of Clinical Oncology ◽

10.1200/jco.2010.28.15_suppl.3081 ◽

2010 ◽

Vol 28 (15_suppl) ◽

pp. 3081-3081 ◽

Cited By ~ 13

Author(s):

S. F. Jones ◽

R. B. Cohen ◽

J. C. Bendell ◽

C. S. Denlinger ◽

R. D. Harvey ◽

...

Keyword(s):

Monoclonal Antibody ◽

Growth Factor ◽

Hepatocyte Growth Factor ◽

Phase I ◽

Dose Escalation ◽

Dose Escalation Study ◽

Hepatocyte Growth

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Phase I, first-in-human, open-label, dose-escalation study of U3-1565, a fully human anti-HB-EGF monoclonal antibody, in patients with advanced solid tumors.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.2519 ◽

2013 ◽

Vol 31 (15_suppl) ◽

pp. 2519-2519 ◽

Cited By ~ 1

Author(s):

Kathleen N. Moore ◽

Johanna C. Bendell ◽

Anthony J. Olszanski ◽

Madhuri Desai ◽

Mendel Jansen ◽

...

Keyword(s):

Monoclonal Antibody ◽

Growth Factor ◽

Solid Tumors ◽

Dose Escalation ◽

Tumor Growth Inhibition ◽

Advanced Solid Tumors ◽

Open Label ◽

Dose Escalation Study ◽

Label Dose ◽

Anti Tumor Activity

2519 Background: Heparin-binding epidermal growth factor-like growth factor (HB-EGF) is an EGF family member and a ligand for EGFR and Her4. U3-1565 is a fully human anti-HB-EGF monoclonal antibody with preclinical anti-tumor and anti-angiogenesis activity. In this study, we evaluated safety, tolerability, immunogenicity, pharmacokinetics (PK), pharmacodynamics (PD), and anti-tumor activity of U3-1565 in patients with advanced solid tumors refractory to standard treatment. Methods: The 3+3 method of enrollment and dose-escalation was used to test U3-1565 at 2, 8, 16, and 24 mg/kg once every two weeks (with the second dose given three weeks after the first), and at 24 mg/kg weekly. Results: 15 patients (11 females, 4 males; median age 62 (range 47-77) years; 5 CRC, 5 NSCLC, 3 ovarian and 2 other cancer) were enrolled, 3 in each dose level cohort. No dose-limiting toxicity was observed and a maximum tolerated dose was not reached. The highest administered dose of 24 mg/kg weekly generated Cmin above the predetermined target concentration corresponding to Cave resulting in 90% preclinical tumor growth inhibition. U3-1565 was safe and well tolerated with related AE consisting of infrequent and non-dose-related G2 (fatigue, anemia, and appetite loss, seen in 20, 13, and 7% of cases, respectively) and G1 toxicities. No anti-U3-1565 antibody was detected. U3-1565 showed bi-exponential disposition with Cmax and AUC increasing proportional to the dose across all dosing regimens. 13 patients discontinued the study, 12 due to progressive disease and 1 due to non-drug-related AE. After 6 months on study, 2 patients entered study extension phase: A 77 year-old female with NSCLC given 24 mg/kg every two weeks, showed SD (best SLD change -3%) for 26 weeks before progression; and a 76 year-old female with CRC given 24 mg/kg weekly, showed PR (best SLD change -35%) and remains on treatment after 71 weeks. Conclusions: U3-1565 is safe and well tolerated up to 24 mg/kg weekly. Anti-tumor activity was observed and is being further explored in an open-label, dose-expansion study. Clinical trial information: NCT0129041.

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