| Eligibility |
Inclusion Criteria
- Confirmed diagnosis of:
- For the monotherapy cohorts: Inoperable, locally advanced or metastatic breast cancer,
NSCLC, CRC, ovarian cancer, or acral melanoma that is refractory to standard therapy
or for which no standard therapy exists. Participants who are considered intolerant of
or ineligible for standard therapy(ies), as well as participants who have been offered
but refused standard therapy(ies), may also be eligible.
- For the pembrolizumab combination therapy cohort: Inoperable, locally advanced or
metastatic NSCLC, CRC (only MSI-H or dMMR), melanoma (with the exception of uveal
melanoma), HCC, HNSCC, ESCC,UC, or TNBC with prior or ongoing anti-PD-1 or anti-PD-L1
treatment and have progressed radiographically or have achieved stable disease for a
minimum of two months and who, in the judgment of their treating physicians, could
benefit from a combination of ATRC-101 and pembrolizumab . The anti-PD-1/anti-PD-L1
therapy must be FDA approved for their cancer indication at the time of screening.
Patients with the tumor types eligible for monotherapy that are TMB-H, MSI-H or dMMR
and have had an unsatisfactory response to anti-PD-1/anti-PD-L1 therapy may enroll for
the pembrolizumab combination, and additional indications that have been identified as
ATRC-101 target positive and are FDA approved for pembrolizumab may be added following
discussion with the study Medical Monitor.
1. Individuals with BRAF mutant melanoma must have received BRAF inhibitors alone or
in combination with a MEK inhibitor, if indicated.
2. Individuals with NSCLC should have received platinum-based therapy unless
contraindicated
- For the PLD combination therapy cohort: Inoperable, locally advanced or metastatic
high-grade serous epithelial ovarian, fallopian tube, or primary peritoneal cancer
that is platinum resistant, defined as progression during or within 6 months of the
last dose of platinum-based chemotherapy OR breast cancer that is refractory to other
standard therapies.
- Measurable disease based on RECIST 1.1, as assessed by the local site
investigator/radiologist. As per RECIST, lesions situated in an area treated with
radiation or other loco-regional therapy are considered measurable only if progression
has been demonstrated in such lesions following loco-regional therapy.
- Eastern Cooperative Oncology Group (ECOG) performance status of 0-1
- Adequate organ and marrow function (i.e., without chronic, ongoing growth factor or
transfusion support) at Screening as defined by the following laboratory parameters
via central laboratory results:
- Absolute neutrophil count (ANC)
1. For monotherapy and pembrolizumab combination therapy cohorts: = 1000/µL
2. For PLD combination therapy cohort: = 1500/µL
- Platelet count = 75,000/µL
- Hemoglobin = 9.0 g/dL
- PT/INR, aPTT = 1.5 x ULN unless participant is receiving a stable dose of therapeutic
anticoagulation
- Albumin = 3.0 g/dL
- Creatinine clearance or eGFR = 30 mL/min as estimated by the Cockcroft-Gault equation
- AST/ALT = 2 x ULN. If documented liver metastases, then = 5X ULN
- Bilirubin
1. For monotherapy and pembrolizumab combination therapy cohorts: = 2 x ULN; or
bilirubin = 3 x ULN if due to Gilbert's or Crigler-Najjar disease
2. For PLD combination therapy cohort: = ULN
- Available representative tumor specimens in paraffin blocks (preferred) or = 20
unstained slides (serial sections), with an associated pathology report, obtained
after last systemic anticancer therapy and within 60 days prior to the planned first
dose of investigational product (Cycle 1-Day 1). If fewer than 20 unstained slides are
available, a discussion with the Medical Monitor is required prior to enrollment. If
an archived sample is not available, participant must have a tumor that is amenable to
biopsy without unacceptable risk of a major procedural complication and consent to
have a tumor biopsy. Tumor lesions used for biopsy should not be lesions used as
RECIST 1.1 target lesions unless there are no other lesions suitable for biopsy. If a
RECIST target lesion is used for biopsy, the lesion must be = 2 cm in longest
diameter. Fine-needle aspirates, cell pellets from pleural effusions, ascites, and
bone metastases are not acceptable.
1. For the pembrolizumab combination therapy cohort: A biopsy collected within 60
days of the planned first dose of investigational product while the participant
is receiving anti-PD-1/anti-PD-L1 therapy is acceptable.
2. For target-enriched expansion cohorts, enrollment will be limited to participants
with pretreatment tumor biopsies demonstrating ATRC-101 target expression above a
predefined threshold by IHC at a central laboratory.
- Women of childbearing potential (WOCBP) and fertile males with partners who are WOCBP
must use highly effective contraception (per CTFG 2014) from first dose and through 90
days after final dose of investigational product
- Willing and able to provide written informed consent and able to comply with all trial
procedures
Exclusion Criteria
Individuals who meet any of the following criteria are not eligible to participate in this
trial:
- Disease that is suitable for local therapy administered with curative intent.
- Malignant disease other than the malignancy to be investigated in this trial within
the last 5 years with the exception of:
a. malignancies previously treated with curative intent with a 5-year OS rate >90%
(consultation with the Medical Monitor is required prior to enrollment).
- Autoimmune disease requiring systemic treatment (e.g., with disease modifying agents,
corticosteroids, or immunosuppressive drugs) in the past 2 years. Hormone replacement
therapy (e.g., insulin, thyroxine, and replacement-dose hydrocortisone) is not
considered systemic treatment for the autoimmune disease.
- Active or prior paraneoplastic neurologic disorder of the central nervous system (CNS)
or history of leptomeningeal disease
- Prior allogenic hematopoietic or solid organ transplant, including allogeneic cellular
therapy (e.g., allogeneic chimeric antigen receptor (CAR)-modified T cells).
Allogeneic bone grafts are not exclusionary.
- Clinically significant cardiovascular disease, e.g., cerebral vascular accident/stroke
or myocardial infarction, within 6 months prior to first dose of investigational
product, unstable angina, congestive heart failure (New York Heart Association = Class
III), or unstable cardiac arrhythmia requiring medication
- For the PLD Combination Therapy Cohort:
1. Any history of documented congestive heart failure (CHF), arrhythmia, or
uncontrolled hypertension (systolic BP > 200 mmHg or diastolic BP > 100 mmHg)
2. Left ventricular ejection fraction measure by echocardiography or multigated
radionuclide acquisition (MUGA) below normal limits for the institution
- Presence of active, symptomatic, or untreated CNS metastasis; or CNS metastasis that
requires local directed therapy or increasing doses of corticosteroids within the 2
weeks prior to the planned first dose of investigational product. Individuals with
treated and/or asymptomatic CNS disease may be enrolled if neurologically stable over
the prior 2 weeks (and after consultation with the Medical Monitor) provided there is
measurable disease (RECIST 1.1) outside of the CNS and there is no ongoing requirement
for corticosteroids to manage the disease
- HIV infection with an AIDS-defining opportunistic infection within the past 12 months
or with a CD4+ T cell count <350/µL
- Hepatitis B surface antigen (HbsAg) positive OR Hepatitis B core antibody (anti-HBc or
HBcAb) positive and HBV viral load above the lower limit of quantification
- Hepatitis C antibody positive with HCV viral load greater than or equal to the lower
limit of quantification
- Infection requiring intravenous antibacterial, antiviral, or antifungal therapy within
2 weeks prior to the planned first dose of investigational product
- Ongoing = Grade 2 toxicity(ies) due to a previously administered anticancer agent with
the following exceptions:
1. Grade 2 neuropathy or alopecia
2. For the monotherapy cohorts: Grade 2 immune-related endocrinopathy attributed to
a checkpoint inhibitor and controlled with hormone replacement alone
- Treatment with biological agents (including monoclonal antibodies and cytokines)
within 28 days of the planned first dose of investigational product with the following
exception:
a.For the pembrolizumab combination therapy cohort: -Anti-PD-1/anti-PD-L1 treatment
within 28 days of the planned first dose of investigational product.
- Treatment with radiation, chemotherapy or anticancer small molecule therapy within 14
days or 5 half-lives (whichever is longer) prior to the first dose of investigational
product. Treatment with nitrosoureas or mitomycin C require a 42-day washout prior to
the planned first dose of investigational product
- For the PLD combination therapy cohort:
1. Prior treatment with PLD
2. Prior treatment with doxorubicin or other anthracycline at cumulative doses
greater than 300mg/m2.
1. Anthracycline equivalent doses: 1 mg Doxorubicin = 1.8 mg Epirubicin = 0.3 mg
Mitoxantrone = 0.25 mg Idarubicin
3. Anthracyclines or anti-HER2 agents, if last dose was administered < 1 year before
enrollment
4. Prior mediastinal irradiation > 3500 cGY
- Receipt of any investigational drug or device not otherwise specified above within 28
days or 5 half-lives (whichever is longer) prior to the planned first dose of
investigational product
- Pregnant or breastfeeding; negative pregnancy status in WOCBP must be confirmed by
serum pregnancy test at Screening
- History of = Grade 3 infusion-related reaction associated with antibody
administration, or:
1. For the monotherapy cohorts: Known allergy/intolerance to ATRC-101 or its
excipients
2. For the pembrolizumab combination therapy cohort: Known allergy/intolerance to
ATRC-101, anti-PD-1 or anti-PD-L1, , or their excipients
3. For the PLD combination therapy cohort: Known allergy/intolerance to ATRC-101,
doxorubicin, or to the excipients of ATRC-101 or PLD
- Major surgery or significant traumatic injury occurring within 28 days prior to the
planned first dose of investigational product. If major surgery occurred > 28 days
prior to Cycle 1-Day 1, individual must have recovered adequately from the toxicity
and/or complications from the intervention prior to Cycle 1-Day 1
- Prior treatment with ATRC-101
- Intercurrent illness that is either life-threatening or of clinical significance such
that it might limit compliance with trial requirements, or in the Investigator's
assessment would place the participant at an unacceptable risk for participation.
Uncontrolled pleural effusion, pericardial effusion or ascites requiring recurrent
drainage procedures is exclusionary
- Receipt of a live, attenuated vaccine within 28 days of planned Cycle 1-Day 1.
Examples of live vaccines include, but are not limited to, the following: measles,
mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus
Calmette-Guerin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection
are generally inactivated flu vaccines and are allowed. Intranasal influenza vaccines
(e.g. FluMist) are live attenuated vaccines and are not allowed.
Replication-incompetent viral, mRNA, subunit, conjugate, and toxoid vaccines are
allowed.
- COVID-19 (SARS-CoV-2) pandemic consideration: The COVID-19 vaccination should not be
delayed; however, caution should be exercised when combining vaccination with cancer
therapy, particularly immunotherapy. The COVID-19 vaccines can cause transient
lymphadenopathy and potentially impact assessment of disease burden during screening
and/or on-study. To allow correct interpretation and reduce equivocal findings,
investigators should discuss with the participant appropriate timing and selection of
anatomic site of vaccination (alternative) with respect to imaging scans (MRI or CT).
Screening scans should be acquired before the first dose of a COVID-19 vaccine or 4-6
weeks after the second dose of the vaccine. Because cancer patients are considered
vulnerable population, after COVID-19 vaccination there is also a potential for
heightened immune related adverse events including CRS. Investigators should use
judgement when evaluating and managing potentially overlapping adverse events and in
establishing causality with the study treatment (Schönrich and Raftery 2019; Desai et
al. 2021; Edmonds et al. 2021; Indini et al. 2021)
For the pembrolizumab combination therapy cohort ONLY:
- Experienced = Grade 3 immune related adverse events while on immunotherapy prior to
enrollment
- Have not recovered from Grade 2 immune related adverse events attributed to
immunotherapy to Grade 1 or baseline prior to enrollment.
- NSCLC with epidermal growth factor receptor (EGFR) or anaplastic lymphoma receptor
tyrosine kinase (ALK) genomic tumor alterations
- Isolated intracranial relapse
- Interstitial lung disease or active, non-infectious pneumonitis
- Signs and symptoms consistent with clinically significant, decreased pulmonary
function: (1) blood saturation oxygen level (SpO2) < 90% at rest on room air; (2)
dyspnea at rest (CTCAE v. 5.0 = Grade 3) or supplemental oxygen used to maintain
adequate oxygenation within 14 days prior to the planned first dose of investigational
product
- Ongoing immune-related toxicity or immune-related toxicity requiring systemic
corticosteroids for 30 or more consecutive days for a prior immune related adverse
event before initiation of study treatment
For the PLD combination therapy cohort ONLY:
•Prior drug-induced cardiotoxicity, defined as a sustained decrease in the ejection
fraction (EF) of > 15%.
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