A Phase I Dose Escalation Study of PT-112 in Patients with Relapsed or Refractory Multiple Myeloma
Authors: Kourelis Taxiarchis , Ailawadhi Sikander , Vogl Dan T. , Cooper Dennis , Ames Tyler D , Yim Christina Y , Price Matthew R , Jimeno Jose J , Bergsagel P. Leif 
Published: November 2020

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.