CTEP #10512: A Phase 2 Randomized Study of the BER Inhibitor TRC102 in Combination with Standard Pemetrexed-Platinum-Radiation in Stage III Non-Squamous Non-Small Cell Lung Cancer
Primary Objective
To improve progression-free survival (PFS) from 56% with current standard of care (chemoradiation followed by consolidative durvalumab) to 75% at one year with the proposed combination followed by consolidative durvalumab.
Secondary Objectives
To determine overall survival with the proposed combination therapy.
To assess the incidence of grade 3 or higher pneumonitis and other toxicities.
CISPLATIN
- Rutgers Cancer Institute of New Jersey
Inclusion Criteria
- Patients must have histologically or cytologically confirmed adenocarcinoma or large
cell carcinoma of the lung with confirmation by immunohistochemistry (histologic
tissue diagnosis is preferred, but cytology is acceptable).
- Patients must have stage IIIA, IIIB or IIIC disease according to the 8th tumor,
node, metastasis (TNM) staging classification and to be considered appropriate
candidates for aggressive chemoradiotherapy.
- Patients must have measurable disease, defined as at least one lesion that can be
accurately measured in at least one dimension (longest diameter to be recorded for
non-nodal lesions and short axis for nodal lesions) as >= 20 mm (>= 2 cm) by chest
x-ray or as >= 10 mm (>= 1 cm) with CT scan, MRI, or calipers by clinical exam.
- Patients must have newly diagnosed NSCLC, with no prior overlapping radiation
therapy delivered for locally advanced NSCLC. Prior stereotactic radiation therapy
for stage I lung cancer without overlapping is allowed. Prior systemic
antineoplastic therapy is allowed, as deemed appropriate by the treating physician.
Prior surgery is allowed.
- Age >= 18 years. Because no dosing or adverse event data are currently available on
the use of TRC102 in combination with pemetrexed, cisplatin, and durvalumab in
patients < 18 years of age, children are excluded from this study.
- Body weight > 30 kg with acceptable nutritional status based on evaluation by
treating physician.
- Eastern cooperative oncology group (ECOG) performance status =< 1 (Karnofsky >=
70%).
- Leukocytes >= 3,000/mcL.
- Hemoglobin >= 9.0 g/dL.
- Absolute neutrophil count >= 1,500/mcL.
- Platelets >= 150,000/mcL.
- Serum bilirubin within normal institutional limits (0 - 1.2 mg/ dl). (This will not
apply to patients with confirmed Gilbert's syndrome [persistent or recurrent
hyperbilirubinemia that is predominantly unconjugated in the absence of hemolysis or
hepatic pathology], who will be allowed only in consultation with their physician.).
- Aspartate aminotransferase (AST)(serum glutamic oxaloacetic transaminase [SGOT]) =<
2.5 x institutional upper limit of normal (=< 39 U/L).
- Alanine aminotransferase (ALT)(serum glutamate pyruvate transaminase [SGPT]) =< 2.5
x institutional upper limit of normal (=< 52 U/L).
- Creatinine =< 1.3 mg/dL.
- Measured creatinine clearance >= 60 mL/min OR glomerular filtration rate (GFR) >= 50
mL/min/1.73 m^2.
- Acceptable pulmonary function as assessed by treating physician.
- Evidence of post-menopausal status or negative urinary or serum pregnancy test for
female pre-menopausal patients. Women will be considered post-menopausal if they
have been amenorrheic for 12 months without an alternative medical cause. The
following age-specific requirements apply:
- Women < 60 years of age would be considered post-menopausal if they have been
amenorrheic for 12 months or more following cessation of exogenous hormonal
treatments and if they have luteinizing hormone and follicle-stimulating
hormone levels in the post-menopausal range for the institution or underwent
surgical sterilization (bilateral oophorectomy or hysterectomy).
- Women >= 60 years of age will be considered post-menopausal.
- Life expectancy >= 12 months.
- Patients who are human immunodeficiency virus (HIV) positive may participate IF they
meet the following eligibility requirements:
- They must be stable on their anti-retroviral regimen with evidence of at least
two undetectable viral loads within the past 6 months on the same regimen; the
most recent undetectable viral load must be within the past 12 weeks.
- They must have a CD4 count of greater than 250 cells/mcL over the past 6 months
on this same anti-retroviral regimen and must not have had a CD4 count < 200
cells/mcL over the past 2 years, unless it was deemed related to the cancer
and/or chemotherapy induced bone marrow suppression.
- For patients who have received chemotherapy in the past 6 months, a CD4
count < 250 cells/mcL during chemotherapy is permitted as long as viral
loads were undetectable during this same chemotherapy.
- They must have an undetectable viral load and a CD4 count >= 250 cells/mcL
within 7 days of enrollment.
- They must not be currently receiving prophylactic therapy for an opportunistic
infection and must not have had an opportunistic infection within the past 6
months.
- HIV-infected patients should be monitored every 12 weeks for viral load and CD4
counts.
- For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV
viral load must be undetectable on suppressive therapy, if indicated.
- Patients with a history of hepatitis C virus (HCV) infection must have been treated
and cured. For patients with HCV infection who are currently on treatment, they are
eligible if they have an undetectable HCV viral load.
- Patients with known history or current symptoms of cardiac disease, or history of
treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac
function using the New York Heart Association functional classification. To be
eligible for this trial, patients should be class 2B or better.
- The effects of TRC102 on the developing human fetus are unknown. For this reason and
because biochemical inhibitors of the BER pathway agents as well as other
therapeutic agents used in this trial are known to be teratogenic, women of
child-bearing potential and men must agree to use adequate contraception (hormonal
or barrier method of birth control; abstinence) prior to study entry, for the
duration of study participation, and for 6 months after completion of durvalumab
monotherapy. Should a woman become pregnant or suspect she is pregnant while she or
her partner is participating in this study, she should inform her treating physician
immediately. Men treated or enrolled on this protocol must also agree to use
adequate contraception prior to the study, for the duration of study participation,
and 6 months after completion of durvalumab administration, if having sex with women
of childbearing potential.
- Ability to understand and the willingness to sign a written informed consent
document. Participants with impaired decision-making capacity who have a
legally-authorized representative (LAR) and/or family member available will also be
eligible.
- Patients with actionable mutations are eligible. Treatment with durvalumab during
consolidative phase will be at physician discretion.
- Patients with prior stage I/II non-small cell lung cancer treated with surgery are
eligible. Patients with prior stage I NSCLC treated with stereotactic body
radiotherapy (SBRT) without overlapping radiation fields would also be eligible.
Patients with prior chemotherapy are eligible, at physician's discretion.
Exclusion Criteria
- Patients who have not recovered from adverse events due to prior anti-cancer therapy
(i.e., have residual toxicities > grade 1) with the exception of alopecia.
- Patients who are receiving any other investigational agents.
- Patients with treated brain metastases are not eligible as the study is for stage
III disease only.
- Patients with new or progressive brain metastases (active brain metastases) or
leptomeningeal disease are not eligible as the study includes only stage III
disease.
- History of allergic reactions attributed to compounds of similar chemical or
biologic composition to TRC102 or other agents used in study.
- Patients with uncontrolled intercurrent illness, including but not limited to,
ongoing or active infection, symptomatic congestive heart failure, uncontrolled
hypertension, unstable angina pectoris, cardiac arrhythmia, interstitial lung
disease, serious chronic gastrointestinal conditions associated with diarrhea, or
psychiatric illness/social situations that would limit compliance with study
requirement, substantially increase risk of incurring AEs or compromise the ability
of the patient to give written informed consent.
- Patients with psychiatric illness/social situations that would limit compliance with
study requirements.
- Pregnant women are excluded from this study because TRC102 is a biochemical
inhibitor of the BER pathway and durvalumab is an anti-PDL1 antibody, agents with
the potential for teratogenic or abortifacient effects. Because there is an unknown
but potential risk for adverse events in nursing infants secondary to treatment of
the mother with TRC102 or durvalumab, breastfeeding should be discontinued if the
mother is treated with TRC102 or durvalumab. These potential risks may also apply to
other agents used in this study.
- Women of child-bearing potential and men must agree to use adequate
contraception (hormonal or barrier method of birth control; abstinence) prior
to study entry, for the duration of study participation, and for 6 months after
durvalumab monotherapy. Should a woman become pregnant or suspect she is
pregnant while she or her partner is participating in this study, she should
inform her treating physician immediately. Men treated or enrolled on this
protocol must also agree to use adequate contraception prior to the study, for
the duration of study participation, and 6 months after completion of
durvalumab.
- Patients with active or prior documented autoimmune or inflammatory disorders
(including inflammatory bowel disease [e.g., colitis or Crohn's disease],
diverticulitis [with the exception of diverticulosis], systemic lupus erythematosus,
Sarcoidosis syndrome, or Wegener syndrome [granulomatosis with polyangiitis, Graves'
disease, rheumatoid arthritis, hypophysitis, uveitis, etc.]). The following are
exceptions to this criterion:
- Patients with vitiligo or alopecia.
- Patients with hypothyroidism (e.g. following Hashimoto thyroiditis) stable on
hormone replacement.
- Any chronic skin condition that does not require systemic therapy.
- Patients without active disease in the last 5 years may be included but only
after consultation with the study physician.
- Patients with celiac disease controlled by diet alone.
- Active infection including tuberculosis (clinical evaluation that includes clinical
history, physical examination and radiographic findings, and tuberculosis [TB]
testing in line with local practice), hepatitis B (known positive HBV surface
antigen [HBsAg] result), or hepatitis C. Patients with a past or resolved HBV
infection (defined as the presence of hepatitis B core antibody [anti-HBc] and
absence of HBsAg) are eligible. Patients positive for hepatitis C (HCV) antibody are
eligible only if polymerase chain reaction is negative for HCV ribonucleic acid
(RNA).
- History of allogenic organ transplantation.
- History of another primary malignancy except for:
- Malignancy treated with curative intent and with no active disease before the
first dose of investigational product (IP) and of low potential risk for
recurrence.
- Adequately treated non-melanoma skin cancer or lentigo maligna without evidence
of disease.
- Adequately treated any carcinoma in situ without evidence of disease.
- Prostate cancer with stable disease with active or prior treatment that will
not interfere with current lung cancer treatment will be eligible.
Please note that we have obtained the inclusion and exclusion criteria information from the National Institutes of Health’s clinical trials web site ClinicalTrials.gov. The listed criteria may not necessarily reflect recent amendments to the protocol and the current criteria.
For further information about clinical trials, please contact us at 732-235-7356.