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  • br Due to fragility fractures observed in the

    2019-11-04


    Due to fragility fractures observed in the IPA, and more so vantictumab, clinical programs, the Sponsor decided to discontinue IPA treatment for all patients in Cohorts 1 and 2 (5 and 10 mg/kg q3w, respectively). Subsequently, patients in Cohorts 3 and 4 were dosed at 2 and 4 mg/kg q3w, respectively. No DLTs or fragility fractures were re-ported in these cohorts, so enrollment of patients into a higher dose co-hort (Cohort 5, 6 mg/kg q3w) proceeded. No DLTs or fragility fractures were reported in Cohort 5, so cohort expansion occurred with an addi-tional 7 patients (Expansion Cohort, 6 mg/kg q3w). Thus, a total of 13 patients were treated with 6 mg/kg q3w IPA. The study was discontinued prematurely and the development of IPA was ultimately 
    stopped based on the incidence of fragility fractures observed in the IPA (6%) and vantictumab (12%) programs [27].
    3.7. Pharmacokinetic and immunogenicity analysis
    IPA serum concentrations in all patients (i.e., drug exposure) were within the expected drug exposure levels, given the dose levels and dos-ing frequencies studied. Formation of anti-drug ML-210 (ADAs) was of very low titer and transient in nature, with an overall immunogenic-ity incidence of 5.4%. There was no evidence that formation of ADAs af-fected drug exposure.
    4. Discussion
    IPA is a recombinant fusion protein (immunoadhesin) consisting of a combination of human Frizzled (FZD) 8 receptor containing the extra-cellular ligand binding domain and human IgG1 Fc fragment that acts as a decoy receptor to inhibit Wnt signaling [25].
    IPA exhibited broad spectrum anti-tumor activity in a range of patient-derived xenografts including pancreatic, liver, breast, colon, ovarian, and melanoma. IPA was tested in a panel of 5 patient-derived EOC models in combination with paclitaxel and was found to be active in 3 of these ovarian tumor xenografts in combination with paclitaxel, producing increased inhibition of tumor growth relative to paclitaxel alone (data on file at OncoMed). In addition, a study in a patient-derived EOC xenograft evaluated the efficacy of IPA in combination with either paclitaxel, nab-paclitaxel, carboplatin, or the combination of carboplatin and paclitaxel. The combination of IPA and each of the taxane-containing regimens led to tumor regression whereas the com-bination with carboplatin alone was less active. The synergy of IPA with taxanes could be explained by the dual effects these drugs have on cell reproduction, blockade of Wnt signaling by IPA and disruption of micro-tubule formation essential for cell division by taxanes [28–30].
    Due to fragility fractures observed in the IPA, and more so vantictumab, clinical programs, the protocol was revised to decrease pollination risk and no further fragility fractures were seen. The MAD after im-plementation of the revised bone safety plan was 6 mg/kg q3w, at which dose level no patient experienced a TEAE that qualified as a DLT or a fragility fracture. Thus, the MTD for IPA was not determined.
    Table 3
    IPA-related treatment-emergent adverse events with CTCAE drade ≥ 3 by system organ class.
    Dose of ipafricept (Q3W) Cohort 1 Cohort 2
    Cohort 3
    Cohort 4
    Cohort 5
    Expansion cohort Overall
    System organ class
    Metabolism and nutrition disorders
    Hypophosphatemia
    Gastrointestinal disorders
    Diarrhea
    Nervous system disorders
    Neuropathy peripheral
    Fig. 1. Plots of maximum increase in β-CTX and concurrent changes in P1NP, BSAP, and osteocalcin. The ‘dots’ represent the means. The ‘whiskers’ represent the 25th and 75th percentiles. Baseline is defined as the last non-missing value prior to first dose of study drug. β-CTX = β-C-terminal telopeptide; P1NP = procollagen type 1 amino-terminal propeptide; BSAP = bone-specific alkaline phosphatase.