APX005M, mFOLFOX Chemotherapy, and Radiation Therapy for the Treatment of Stage II-III Rectal Cancer, The INNATE Trial
This phase II trial investigates how well APX005M, modified (m)FOLFOX chemotherapy regimen (fluorouracil, leucovorin calcium, oxaliplatin), and radiation therapy works in treating patients with rectal cancer. APX005M is a type of immunotherapy called a monoclonal antibody which may help treat cancer by strengthening the immune system. Chemotherapy drugs, such as fluorouracil, leucovorin calcium, and oxaliplatin, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Radiation therapy uses high energy x-rays to kill tumor cells and shrink tumors. The addition of APX005M to mFOLFOX (standard of care chemotherapy for rectal cancer) and radiation therapy may help improve response rates and long-term outcomes in treatment of locally advanced rectal cancer patients.
Inclusion Criteria
- Willing and able to provide written informed consent
- Pathologic diagnosis of rectal adenocarcinoma
- Stage III or stage II with at least 1 of the following high-risk features: * Distal (< 1 cm from anal ring) * cT4 or within 3 mm of mesorectal (MR) fascia * Not candidate for sphincter preservation * Extramural venous invasion
- No prior treatment for rectal adenocarcinoma
- Eastern Cooperative Group (ECOG) performance status of 0-1
- White blood cells (WBC) >= 3,000/mL (within 21 days of eligibility confirmation)
- Absolute neutrophil count (ANC) WBC >= 1,500/mL (within 21 days of eligibility confirmation)
- Platelets (PLT) >= 100,000/mL (within 21 days of eligibility confirmation)
- Total bilirubin (T Bili) =< 1.5 x upper limit of normal (ULN) (within 21 days of eligibility confirmation)
- Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 2.5 x ULN (within 21 days of eligibility confirmation)
- Creatinine not above ULN, or creatinine clearance >= 60 mL/min/1.73 m^2 for participants with creatinine levels above institutional normal (within 21 days of eligibility confirmation)
- Female participants of childbearing potential (FOCBP) must have a negative serum or urine pregnancy test (per institutional standards) within 72 hours prior to the start of study drug. FOCBP must agree to use highly-effective method(s) of contraception during the study and for 90 days after the last dose of study drugs. FOCBP are those who have not been surgically sterilized or have not been free from menses for > 1 year without an alternative medical cause
- Male participants must agree to use an adequate method of contraception starting with the first dose of study therapy through 90 days after the last dose of study drugs
Exclusion Criteria
- Distant nodal disease (retroperitoneal nodes) including inguinal nodes, or any metastatic disease by computed tomography (CT) or positron emission tomography (PET)
- Prior radiation therapy (RT) to the pelvis
- Uncontrolled comorbid illness or condition including an active infection, congestive heart failure, unstable angina, cardiac arrhythmia, or psychiatric illness that would limit compliance with the study requirements
- Prior treatment with any anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways
- Any positive history for human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS), human T-cell leukemia virus (HTLV), hepatitis B or hepatitis C virus indicating acute or chronic infection
- Any active known or suspected autoimmune disease. Participants with vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll
- Any condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days prior to the first dose of study drug. Inhaled steroids and adrenal replacement steroid doses up to 10 mg daily prednisone equivalent are permitted (although not encouraged) in the absence of active autoimmune disease
- Malignancy in the past 3 years that required active treatment except locally curable cancers or cancers deemed by the treating physicians to not impact the subject's survival duration
- Participants receiving any other investigational agent, standard antineoplastic agents, or immunosuppressive agents
- Known history of interstitial lung disease
- Received live vaccine within 6 weeks prior to randomization
- Psychiatric illness/social situations that would limit consenting and compliance with study requirements
- Participants who are pregnant or nursing due to the potential for congenital abnormalities and the potential of this regimen to harm nursing infants
- Patient is not a candidate for the full treatment regimen
Study sponsor and potential other locations can be found on ClinicalTrials.gov for NCT04130854.
PRIMARY OBJECTIVE:
I. To determine the pathologic complete response (pCR) rate of the combined treatment modality.
SECONDARY OBJECTIVES:
I. To evaluate overall survival (OS), defined as the time between date of randomization and the date of death due to any cause.
II. To evaluate disease-free survival (DFS), defined as the time between date of definitive surgery and the first date of documented disease progression, or death.
III. To evaluate the rate of clinical complete response (cCR), defined as the rate of all tumor resolution on magnetic resonance imaging (MRI), endoscopy, and digital rectal exam.
IV. To evaluate the rate of R0 resection, defined as a negative surgical margin at time of total mesorectal excision.
V. To evaluate the safety and tolerability of the study regimen, including acute and late toxicity as measured according to Common Terminology Criteria for Adverse Events (CTCAE) version (v)5.0.
VI. To evaluate the rate of local failure, defined as recurrence of disease in the pelvis.
VII. To evaluate the rate of distant failure, defined as development of disease outside of the pelvis.
VIII. To describe imaging response and clinical response from initial clinical stage to the clinical restaging evaluation prior to surgery which includes a non-contrast pelvic MRI.
EXPLORATORY OBJECTIVES:
I. To evaluate the immunologic response surrogates of treatment with immunohistochemical staining of CD8 T cells and PD-L1 expression.
II. To evaluate circulating cell free deoxyribonucleic acid (DNA) pre and post therapy to evaluate it as a surrogate for response.
III. To evaluate specific immune mechanistic responses to characterize radiation, chemotherapy, and sotigalimab (APX005M) biologic responses using next generation sequencing methodologies, metabolic analyses, and multiplexed immunohistochemistry technology.
IV. To compare quality of life in patients randomized to short course radiotherapy, chemotherapy and surgery versus short course radiotherapy, chemotherapy surgery plus CD40 agonist using the European Organization for Research and Treatment of Cancer (EORTC) quality of life questionnaire.
OUTLINE: Patients are randomized to 1 of 2 arms.
ARM I: Patients undergo radiation therapy daily on days 1-5. Beginning 21 days after completion of radiation therapy, patients receive mFOLFOX on day 1, which consists of oxaliplatin intravenously (IV) over 2 hours, leucovorin calcium IV over 2 hours, and fluorouracil IV over 2-4 minutes and infusion over 46 hours. Treatment with mFOLFOX repeats every 14 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients also receive sotigalimab IV over 1 hour on day 3 of radiation therapy, and on day 3 of cycles 1-5 of mFOLFOX in the absence of disease progression or unacceptable toxicity.
ARM II: Patients undergo radiation therapy daily on days 1-5. Beginning 21 days after completion of radiation therapy, patients receive mFOLFOX on day 1, which consists of oxaliplatin IV over 2 hours, leucovorin calcium IV over 2 hours, and fluorouracil IV over 2-4 minutes and infusion over 46 hours. Treatment with mFOLFOX repeats every 14 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up every 3-6 months for up to 3 years.
Trial PhasePhase II
Trial Typetreatment
Lead OrganizationUT Southwestern/Simmons Cancer Center-Dallas
Principal InvestigatorTodd Aguilera
- Primary ID SCCC-08219; STU-2019-1492
- Secondary IDsNCI-2020-05715
- ClinicalTrials.gov IDNCT04130854