We performed two parallel phase I trials, a monotherapy study with ABR-217620 (MONO study) and a study in combination with docetaxel (COMBO study).
Thirty-nine patients (20 with NSCLC, eight with PC, and 11 with RCC) were enrolled () between April 2003 and November 2006. Thirty-two patients received one cycle, six patients received two cycles, and one patient received three cycles across multiple dose levels (range, 0.5 to 27.4 μg/kg). Median age of patients was 54 years (range, 37 to 75 years). Most were white (> 90%) and had a favorable ECOG PS of 0 (46%) or 1 (51%). Four patients had received no prior chemo- or immunotherapy, 16 patients had received one regimen, and 19 patients had received ≥ two chemo- or immunotherapy regimens. Median number of prior chemo- or immunotherapy regimens was 1 (range, 0 to 11 prior regimens). Sixteen patients had received prior radiation therapy. Twenty patients had stage IV disease.
Thirteen NSCLC patients were enrolled () between October 2005 and September 2006. Median age was 59 years (range, 38 to 74 years). Eleven patients had stage IV disease. Median number of prior therapies was 1 (range, 0 to 3 prior therapies). Five patients had ECOG PS 1. Three patients each received ABR-217620 10.3 or 16.5 μg/kg. Seven received 22 μg/kg.
The adverse effects of ABR-217620 are presented in . There was one death in the MONO study due to progressive disease. In the COMBO study, two deaths occurred, one due to neutropenic sepsis (felt related to docetaxel) and another due to hemoptysis related to tumor necrosis. Both patients had a diagnosis of NSCLC and both were treated with 22 μg/kg of ABR-217620 and docetaxel.
DLTs: Most Common Adverse Events and No. of Patients With Adverse Events Displayed by Dose and Tumor Type
The most common drug-related adverse events in the MONO study were fever, nausea, vomiting, diarrhea, chills, and hypotension. There was a dose-dependent, transient blood pressure decrease during cycle 1, with nadir usually 4 to 6 hours after ABR-217620 administration on day 1, together with a dose-dependent, transient increase in mean pulse and body temperature. Changes in laboratory parameters and vital signs in treatment cycle 1 were independent of individual pretreatment anti-SAg levels. In patients receiving a second cycle, the same effects were observed as in cycle 1, although consistently to a lesser extent.
The most common toxicities in the COMBO study were fever, hypotension, nausea, and chills, and the same changes in blood pressure, pulse, and temperature as in the MONO study. All of these effects were most evident during treatment cycle 1. Less toxicity occurred in cycle two, probably because of a combination of induced anti-SAg (in some patients) and lower capacity of SAg-activated T lymphocytes to produce cytokines (partial anergy).
In the MONO study, there were no treatment-related effects on hemoglobin or basophils. There was a dose-dependent decrease in WBC, lymphocyte, monocyte, and eosinophil levels 3 hours after drug administration in all patients on days 1 through 5, with return of WBC and eosinophils to baseline by the next day, and normalization of lymphocytes and monocytes on day 6. Neutrophil levels declined transiently 3 hours after drug administration on days 1 through 4 in patients with RCC and NSCLC at ABR-217620 doses higher than 15 μg/kg. Platelet count decreased in a dose-dependent manner on days 1 through 6, increasing by day 12 to above baseline with return to baseline on day 28. In the COMBO study, mean neutrophil counts decreased after each treatment as expected from docetaxel. Docetaxel was reduced (from 75 to 55 mg/m2) for neutropenia in two patients.
In the MONO study, transient increases in liver enzymes (one grade 3) were seen in cycle 1 at higher than 15 μg/kg of ABR-217620. A dose-dependent transient decrease in albumin levels was noted at all dose levels. In the COMBO study, there was a transient increase in liver enzymes in all dose groups during treatment cycle 1 and to a lesser extent during treatment cycle 2.
In the MONO study, DLTs of fever, hypotension, liver toxicity, and acute vascular leak syndrome occurred in six patients at higher than 20 μg/kg of ABR-217620 (four RCC patients and two PC patients). In the COMBO study, one patient at 22 μg/kg ABR-217620 experienced DLT (sepsis-induced toxic shock syndrome) during cycle 1. DLTs were independent of baseline anti-SAg levels, unlike the earlier study with the predecessor drug ABR-214936.12
The formal MTD for patients with NSCLC and PC was 26 μg/kg. The observed DLTs in PC patients occurred at doses very close to the MTD. Thus, 22 μg/kg was chosen as recommended phase 2 dose for NSCLC and PC. The MTD for RCC was 15 μg/kg.
Dose Reductions and Study Discontinuation
There were no ABR-217620 dose reductions in either study. One dose delay for up to 24 hours was allowed per treatment cycle. In the MONO study, reasons for treatment discontinuation included disease progression (n = 24), DLT (n = 6), consent withdrawal (n = 1), investigator decision (n = 3), adverse event (necrotizing pneumonia, n = 1), death from disease (PC, n = 1), initiated another treatment (n = 1, treatment here included two phase I trials with other biologic agents followed by cytotxic chemotherapy), clinical/laboratory progression (n = 1), and completed protocol (n = 1). In the COMBO study, reasons for treatment discontinuation included disease progression (n = 6), DLT (n = 1), consent withdrawal (n = 1), adverse event (tumor necrosis, n = 1), initiated another treatment (n = 1), and completed protocol (n = 3).
Pharmacokinetic parameters and plasma concentration time profiles for ABR-217620 are presented in . Maximum plasma concentrations of ABR-217620 occurred approximately 5 minutes after dosing followed by a rapid decline in plasma concentration with a mean half-life of approximately 1 hour. ABR-217620 showed a small volume of distribution and low plasma clearance (about 0.1 L/kg and 0.1 L/h/kg, respectively) in cycle 1. Pharmacokinetic parameters were unchanged during the treatment cycle and were similar after the first and last dose within a cycle. Pharmacokinetics was linear in the dose range 10 to 27 μg/kg across the three diseases with systemic exposure to ABR-217620 increasing in a dose proportional manner. In most patients there was a low (0 to 100 pmol/mL) to intermediate (100 to 500 pmol/mL) increase in anti-SAg levels after treatment. In general, systemic exposure to ABR-217620 was lower in treatment cycles 2 and 3, presumably from induced anti-SAg. Systemic exposure to docetaxel was not affected by ABR-217620. The severity of adverse events correlated to dose, concentration at 5 minutes after dosing and area under the time-concentration curve (AUC) of ABR-217620. Changes in laboratory parameters (interleukin-2 [IL-2], interferon-γ [IFN-γ], and lymphocytes) and vital signs (body temperature, pulse, and blood pressure) were found to be significantly correlated to AUC of ABR-217620.
Pharmacokinetic Parameters of ABR-217620
ABR-217620 infusion caused a dose-dependent increase of cytokines (peaking 2 to 3 hours after bolus) including IL-2 and IFN-γ (A and B). The induced systemic cytokine levels were greatest after the first treatment. Cytokine production was seen in all treated cancer types and served as a biomarker for T-lymphocyte activation.
Fig 2. ABR-217620 pharmacology. Geometric mean of (A) interleukin-2 (IL-2) and (B) interferon (IFN)-γ levels in plasma at before and 3 hours after first infusion of ABR-217620 in the MONO (ABR-217620 dose escalation monotherapy) study. Renal cell carcinoma (more ...) Selective T-cell expansion.
ABR-217620 caused a pronounced and selective expansion of the superantigen SEA/E-120 reactive T-cell population (TCR-Vβ6.4 expressing T cells) from background levels approximately 5% up to 54% to 64% of T cells with the highest levels observed on day 5 (C). This T-cell compartment then returned to baseline level as expected after a phase of stimulation and expansion.
T-cell infiltration of tumor biopsies post–ABR-217620 treatment.
Tumor biopsies from two patients (both with NSCLC), in the COMBO study were evaluated by immunohistochemistry. Neither patient had received immunomodulatory drugs (eg, IL-2) between their original biopsies (archival tissue) and treatment with the study drug. Both tumors expressed 5T4. Enhancement of T-cell infiltration of tumor after ABR-217620 treatment was evident in both patients. One patient showed increased numbers of CD3-expressing cells (T lymphocytes) adjacent to tumor cells in a biopsy taken on the third day of treatment in cycle 2. The second patient demonstrated massive tumor-associated infiltration of CD3-positive cells and apparent tumor cell destruction on the cycle 2 day 3 biopsy (). Under normal circumstances, there are very few lymphocytes present in most solid tumor unless there is an inflammatory reaction at the tumor site. Thus, we believe that the observed tumor infiltration was due to the study drug.
Fig 3. Immunohistochemistry for T-lymphocyte (anti-CD3) infiltration in biopsies taken before treatment (archival tissue) and at the third day of the second cycle treatment with ABR-217620 for patient number 2. The T lymphocytes stain brown and the arrows indicate (more ...) Immunogenicity.
Baseline human antimouse antibodies levels were negligible with mild increases during and after cycle one. Baseline levels of anti-SAg antibodies were low (D) with only a low (0 to 100 pmol/mL) to moderate (100 to 500 pmol/mL) increase in concentration in approximately 60% of the patients after treatment in the MONO study. This contrasts with the ABR-214936 experience in which higher concentration of anti-SAg antibodies were induced.13
Patients in the COMBO study showed lower increases of anti-SAg antibodies. Exposure to ABR-217620 in both studies was lower in subsequent cycles when antibody levels were ≥ 100 pmol/mL after cycle 1.
In the MONO study, 14 patients (36%) had SD on day 56 (seven NSCLC [25%] and seven RCC [64%]). In the COMBO study, the best overall response was confirmed partial remission for two patients (15%) and SD for five patients (38%). One patient with partial remission received 4 cycles of therapy at 10.3 μg/kg ABR-217620 and the second received 6 cycles of therapy at 22 μg/kg. The latter patient had progressed while receiving prior docetaxel; response continues at 30+ months.