Open label single-arm interventional, non-randomized, phase 1b study of Lintuzumab-Ac225 in combination with pembrolizumab (PEM) or nivolumab (NIVO) in adult patients with locally advanced and metastatic NSCLC or HNSCC. Fifteen eligible subjects will receive a single dose of Lintuzumab-Ac225 at 1.5 μCi/kg every 6 weeks (Q6W/cycle) in combination with either PEM at 200 mg Q3W or NIVO at 240 mg Q2W. Up to 3 cycles of Lintuzumab-Ac225 are allowed as per instructions in the Pharmacy Manual. Lintuzumab-Ac225 will be administrated one day prior to starting PEM or NIVO infusion on weeks 0, 6, and 12. The primary objective is to evaluate the safety and tolerability of Lintuzumab-Ac225 in combination with PEM or NIVO in locally advanced and metastatic NSCLC or HNSCC. Lintuzumab-Ac225: Patients who are enrolled in the study will be
administered a single dose of Lintuzumab-Ac225 at 1.5 μCi/kg every 6 weeks (Q6W/cycle), IV, for up
to 3 cycles of treatment. In patients
whose actual body weight exceeds their ideal body weight (IBW), doses of
Lintuzumab-Ac225 will be calculated based on adjusted body weight (ABW) using
the formulas below: For males: IBW
= (2.3 kg x [inches > 5 ft]) + 50 kg For females:
IBW = (2.3 kg x [inches > 5 ft]) + 45.5 kg ABW
= IBW + [0.4 (actual weight – IBW)] Justification of the dose of
Lintuzumab-Ac225: The dose of Lintuzumab-Ac225 at 1.5 µCi/kg in combination with
PEM or NIVO was selected based on the safety, tolerability profile of a single
agent phase I study of Lintuzumab-Ac225 in relapsed or refractory AML. The
study indicated that therapy for AML with the targeted α-particle generator
Lintuzumab Ac225 was feasible with an acceptable safety profile. The maximum
tolerated dose (MTD) was 3.0 µCi/kg. (Rosenblat,
T. L., McDevitt, M. R., Carrasquillo, J. A., Pandit-Taskar, N., Frattini, M.
G., Maslak, P. G., Jurcic, J. G. (2022) Treatment of patients with acute
myeloid leukemia with the targeted alpha-particle nanogenerator
actinium-225-lintuzumab. Clin Cancer Res.,28(10), 2030-2037.) Supportive care: Prophylactic treatment to mitigate potential nephrotoxicity Due to the short path length of
α-radiation, unbound α-immunoconjugates circulating in blood are unlikely to
cause significant toxicity. In our previous studies, nephrotoxicity has not
been reported. However, α-emitting free daughter nuclides of 225Ac, including
221Fr [t1/2 = 4.8 min], 217At [t1/2 = 32.3 ms], and 213Bi [t1/2 = 45.6 min],
will accumulate and be excreted in the kidney and thus irradiate renal tubular
cells. The kidney is a particularly radiosensitive organ with a low-tolerance
dose for irradiation, and nephrotoxicity, mainly due to 213Bi, may be expected
to be the DLT of Lintuzumab-Ac225. Therefore, therapeutic strategies to protect
renal tissue from internally delivered α-particle irradiation need to be
explored. Patients are required to receive spironolactone
at a dose of 25 mg daily starting 10 days after the first Lintuzumab-Ac225 dose
(C1D10+2 days) until 1 year after last lintuzumab-Ac225 administration, unless
clinically contraindicated. Eplerenone may be used for those who are allergic
to or intolerant of spironolactone. Pembrolizumab (PEM): 200 mg,
IV, Q3W/cycle until progression
Nivolumab (NIVO): 240 mg,
IV, Q2W/cycle until progression Procedures
to be performed at screening will include informed consent; assessment of
inclusion/exclusion criteria; recording of medical, oncology, and concomitant
medications histories; recording of demographics; collection and testing of
tumor tissue samples for PD-L1 assessment, CD33 expression assessment and for
epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK)
mutations, baseline radiographic tumor assessment (CT scan or MRI) and tumor
burden assessment (RECIST 1.1 criteria); chest X-ray; serum pregnancy testing;
12-lead electrocardiogram; complete physical examination including vital signs,
height, and weight assessments; Eastern Cooperative Oncology Group (ECOG)
performance status assessment; adverse event (AE) recording; and laboratory
testing. Blood samples will be obtained for CD33 + MDSC assessment, Lintuzumab-Ac225
pharmacokinetics (PK) and PEM ADA/NIVO ADA evaluation. During
the study treatment period, the following procedures will be performed to assess
efficacy and safety: physical examination, ECOG performance status assessment;
vital signs; laboratory testing, including pregnancy testing for women of
childbearing potential; recording of AEs and concomitant medications. CT scan
or MRI (or positron emission tomography)
for radiographic tumor burden assessment and tumor burden assessment
based on RECIST 1.1 criteria. Blood samples will be obtained for CD33+ MDSC
assessment, Lintuzumab-Ac225 pharmacokinetics (PK) and PEM ADA/NIVO ADA
evaluation. Tumor tissue samples will be
collected for CD33 expression assessment at pre-specified time
points throughout the study. Survival
data will then be collected by phone or at an office visit every 1 month for 12
months and then every 3 months, until death, loss to follow-up. Dosimetry plan for Lintuzumab-Ac225 Dosimetric imaging procedure: Dosimetric imaging of the biodistribution of
Lintuzumab-Ac225 will be performed using an imaging surrogate,
Lintuzumab-In111, at defined time points prior to the therapeutic infusion of
Lintuzumab-Ac225. This provides patient-specific biodistribution data that will
be used for radiation dosimetry calculations. This allows evaluation of the
radiation absorbed dose to tumor, normal organs and tissues of the body per
unit administered radioactivity (millicurie, mCi or megabecquerel, MBq).
Dosimetric imaging will be performed using quantitative SPECT/CT during the
below suggested time points. Imaging procedures and timing: The quantitative SPECT/CT imaging will be performed at 3-4
time points (minimum 3) prior to Lintuzumab-Ac225 infusion. Following infusion
of the imaging surrogate Lintuzumab-In111, images will be acquired within 4
hours post infusion on the day of the Lintuzumab-In111 infusion, and again on
day 2±1 after, day 4±1 after and if feasible 6±1 after the Lintuzumab-In111
infusion (refer to the schedule below). Image data processing:
Data processing comprises the following tasks: identifying
and drawing regions of interest (tumor and normal organs), saving the regions,
applying the regions of interest to the acquired images to obtain count
information, and recording the results as %injected activity for that region at
each imaging time point. These data will then be shared with Actinium
Pharmaceuticals to perform dosimetry calculations. Study Endpoints Primary Endpoints: · Safety: treatment-emergent adverse events,
treatment-related adverse events, and clinically significant changes in vital
signs, physical examinations, electrocardiogram (ECGs), and clinical laboratory
tests Secondary Endpoints: · Objective response rate
(ORR) assessed per RECIST 1.1 criteria · Progression-free survival
(PFS) ·
Overall survival (OS) ·
PK parameters of Lintuzumab-Ac225
including, but not limited to, maximum observed plasma concentration (Cmax),
time to achieve Cmax (tmax), and area under the plasma concentration-time
curve (AUC) Exploratory Endpoints: ·
Duration of overall response (DOR) ·
CD33+ MDSCs in peripheral blood before
and after the study treatment ·
CD33+ MDSCs within the TME before and
after the study treatment Analysis Sets The
analysis of all endpoints, unless noted otherwise, will be conducted on the
Safety Analysis Set defined as all subjects that are enrolled and receive at
least 1 dose of Lintuzumab-Ac225. The PK
Analysis Set will contain all subjects who have received at least 1 dose of the
Lintuzumab-Ac225. These subjects will be evaluated for PK analysis unless the
number of data points required for analysis is not enough, or significant
protocol deviations have affected the data, or if key dosing or sampling
information is missing. Statistical Analysis General
Considerations Descriptive
statistics will be provided for selected demographics, safety, PK, and efficacy.
Descriptive statistics on continuous data will include means, medians, standard
deviations and ranges, while categorical data will be summarized using
frequency counts and percentages. Safety Data Analyses Adverse Events Subject
incidence of all treatment-emergent adverse events will be tabulated by system organ
class and preferred term. The number and percentage of subjects reporting adverse
events will be evaluated overall and by dose level and will also be tabulated
by relationship to study drug. Tables
of fatal adverse events, serious adverse events, and adverse events leading to withdrawal
from investigational product or other protocol-required therapies will also be provided. Clinical Laboratory Tests Clinical
chemistry, hematology, and urinalysis data will be presented and reviewed for each
subject. Values outside the normal laboratory reference ranges will be flagged
as high or low on the listings. Depending on the size and scope of changes in
laboratory data, summaries of laboratory data over time and/or changes from
baseline over time may be provided. Tables of maximum shifts from baseline for
selected laboratory values may also be provided. Vital Signs Vital
signs data will be presented and reviewed for each subject. Depending on the
size and scope of changes, summaries of vital signs data over time and/or
changes from baseline over time may be provided. Electrocardiograms Summaries
over time and/or changes from baseline over time will be provided for all ECG
parameters. Efficacy Endpoint Analyses: The
proportion of subjects with an objective response (CR or PR) with corresponding
exact 90% CI will be calculated using the Clopper-Pearson method (Clopper and
Pearson, 1934). The efficacy endpoints: progression-free survival, overall
survival and duration of response will be presented. A Kaplan-Meier curve will be
presented for PFS and OS with estimates for rates and 90% CI at selected weeks.
Pharmacokinetics Data Analysis
For Lintuzumab-Ac225,
pharmacokinetic parameters including, but not limited to Cmax, tmax,
and AUC will be determined from the concentration-time profile using standard
noncompartmental approaches and considering the profile over the complete
sampling interval. |