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Phase II Randomized Multi-center Trial of Total Neoadjuvant Therapy With and Without CD40 Agonist, APX005M, for Locally Advanced Rectal Adenocarcinoma

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ClinicalTrials.gov Identifier: NCT04130854
Recruitment Status : Not yet recruiting
First Posted : October 18, 2019
Last Update Posted : October 30, 2019
Sponsor:
Collaborator:
Apexigen, Inc.
Information provided by (Responsible Party):
University of Texas Southwestern Medical Center

Brief Summary:
Determine the complete pathologic complete response (pCR) rate in patients with locally advanced rectal adenocarcinoma.

Condition or disease Intervention/treatment Phase
Locally Advanced Rectal Adenocarcinoma Drug: Radiation Therapy 5Gy x 5 days Phase 2

Detailed Description:
A phase II randomized trial 3:2 with continuous safety assessment for at least 6 patients. Interim analysis after 30 patients for early stopping criteria for futility or efficacy. The null hypothesis is that pCR is 16% and to reject the null hypothesis we aim to show a 48% pCR rate using a 5% one sided type 1 error boundary with 80% power. At interim analysis if the test statistic is less than or equal to 2.488 then the trial will be stopped with rejection of the null hypothesis. If the test statistic is less than or equal to 0.442 then we accept the null hypothesis and stop the trial early.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 58 participants
Allocation: Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase II Randomized Multi-center Trial of Total Neoadjuvant Therapy With and Without CD40 Agonist, APX005M, for Locally Advanced Rectal Adenocarcinoma
Estimated Study Start Date : November 1, 2019
Estimated Primary Completion Date : November 1, 2020
Estimated Study Completion Date : November 1, 2020

Arm Intervention/treatment
Experimental: Radiation Therapy 5Gy x 5 days - APX005M 0.3ug/m^2 IV on day 3
On Day 1 of Cycles 1 and 2 of each mFOLFOX treatment, participants will receive another dose of APX005M. The sequence of administration of APX005M in combination with mFOLFOX. In Cycle 3, participants will receive only mFOLFOX. After completing the last planned dose of mFOLFOX, participants will be considered off-protocol directed therapy and undergo planned TME, per institutional standards, and proceed to the follow-up portion of this study.
Drug: Radiation Therapy 5Gy x 5 days
  1. APX005M 0.3 ug/m2 intravenously on day 3 of radiation and on day 3 of cycle 1 and 2 of FOLFOX chemotherapy
  2. Short course radiation therapy 5 Gy x 5 days
  3. Oxaliplatin 85mg/m2 intravenous day 1 of each cycle
  4. Leucovorin 400mg/m2 IV Day 1 of each cycle
  5. 5-FU 2400 mg/m2 continuous infusion over 46 hours of each cycle
Other Name: APX005M

Experimental: Radiation Therapy 5Gy x 5 days
Participants randomized to Arm 2 will receive short-course RT and mFOLFOX regimen, except that participants will not receive any of the study drug. After completing the last planned dose of mFOLFOX, participants will be considered off-protocol directed therapy and undergo planned TME, per institutional standards, and proceed to the follow-up portion of this study.
Drug: Radiation Therapy 5Gy x 5 days
  1. APX005M 0.3 ug/m2 intravenously on day 3 of radiation and on day 3 of cycle 1 and 2 of FOLFOX chemotherapy
  2. Short course radiation therapy 5 Gy x 5 days
  3. Oxaliplatin 85mg/m2 intravenous day 1 of each cycle
  4. Leucovorin 400mg/m2 IV Day 1 of each cycle
  5. 5-FU 2400 mg/m2 continuous infusion over 46 hours of each cycle
Other Name: APX005M




Primary Outcome Measures :
  1. Pathological Complete Response Rate [ Time Frame: 3 years ]
    The primary objective of is to determine the pathologic complete response (pCR) rate of the combined treatment modality.


Secondary Outcome Measures :
  1. Overall Survival [ Time Frame: 3 years ]
    To evaluate overall survival (OS), defined as the time between date of randomization and the date of death due to any cause.

  2. Disease-free Survival [ Time Frame: 3 years ]
    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

  3. Rate of resection [ Time Frame: 3 years ]
    To evaluate the rate of R0 resection, defined as a negative surgical margin at time of total mesorectal excision

  4. Safety [ Time Frame: 3 years ]
    To evaluate the safety and tolerability of the study regimen, including acute and late toxicity as measured according to CTCAE v5.0.

  5. Disease Recurrence [ Time Frame: 3 years ]
    To evaluate the rate of local failure, defined as recurrence of disease in the pelvis

  6. Development of Disease [ Time Frame: 3 years ]
    To evaluate the rate of distant failure, defined as development of disease outside of the pelvis.

  7. Clinical Imaging response [ Time Frame: 3 years ]
    To describe imaging response and clinical response from initial clinical stage to the clinical restaging evaluation prior to surgery which includes a noncontrast pelvic MRI.


Other Outcome Measures:
  1. Immunological Response [ Time Frame: 3 years ]
    To evaluate the immunologic response surrogates of treatment with immunohistochemical staining of CD8 T cells and PD-L1 expression.

  2. Evaluation and Post Therapy [ Time Frame: 3 years ]
    To evaluate circulating cell free DNA pre and post therapy to evaluate it as a surrogate for response.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 99 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. At least 18 years of age. Both men and women and members of all races and ethnic groups will be included.
  2. Willing and able to provide written informed consent
  3. Pathologic diagnosis of rectal adenocarcinoma
  4. Stage III or Stage II with at least 1 of the following high-risk features:

    • Distal (<1cm from anal ring)
    • Bulky cT4 or within 3mm of MR fascia
    • Not candidate for sphincter preservation
    • Extramural venous invasion
  5. Stage IV liver-limited disease with ≤ 3 lesions Note: up to 6 participants with liver-limited disease are eligible to participate
  6. No prior treatment for rectal adenocarcinoma
  7. Eastern Cooperative Group (ECOG) performance status of 0-1.
  8. Laboratory values supporting acceptable organ and marrow function within 30 days of eligibility confirmation. Defined as follows:

    • WBC ≥ 3,000/mL;
    • ANC WBC ≥ 1,500/mL;
    • PLT ≥ 50,000/mL;
    • T Bili ≤ 1.5 x upper limit of normal (ULN);
    • AST/ALT ≤ 2.5 x ULN;
    • Creatinine not above ULN, or creatinine clearance ≥60 mL/min/1.73 m2 for participants with creatinine levels above institutional normal.
  9. 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 (Appendix A) during the study and for 6 months 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.

  10. Male participants must agree to use an adequate method of contraception (Appendix A) starting with the first dose of study therapy through 3 months after the last dose of study drugs.

Exclusion Criteria:

  1. Distant nodal disease (retroperitoneal nodes), or any metastatic disease by CT or PET (except liver limited disease as allowed in 4.1.5).
  2. Prior RT to the pelvis.
  3. Uncontrolled comorbid illness or condition including an infection, congestive heart failure, unstable angina, cardiac arrhythmia, or psychiatric illness that would limit compliance with the study requirements.
  4. 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.
  5. Any positive history for HIV/AIDS, HTLV, hepatitis B or hepatitis C virus indicating acute or chronic infection.
  6. 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.
  7. 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.
  8. Participants receiving any other investigational or standard antineoplastic agents.
  9. Psychiatric illness/social situations that would limit consenting and compliance with study requirements.
  10. Participants who are pregnant or nursing due to the potential for congenital abnormalities and the potential of this regimen to harm nursing infants.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04130854


Contacts
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Contact: Samantha Mannala, BS 214-648-1873 Samantha.Mannala@UTSouthwestern.edu

Locations
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United States, Texas
Simmons Comprehensive Cancer Center at University of Texas Southwestern Medical Center - Dallas
Dallas, Texas, United States, 75390
Sponsors and Collaborators
University of Texas Southwestern Medical Center
Apexigen, Inc.
Investigators
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Principal Investigator: Todd Aguilera, MD UT Southwestern Medical Center

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Responsible Party: University of Texas Southwestern Medical Center
ClinicalTrials.gov Identifier: NCT04130854     History of Changes
Other Study ID Numbers: STU 2019-1492
First Posted: October 18, 2019    Key Record Dates
Last Update Posted: October 30, 2019
Last Verified: October 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Adenocarcinoma
Rectal Neoplasms
Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Colorectal Neoplasms
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Digestive System Diseases
Gastrointestinal Diseases
Intestinal Diseases
Rectal Diseases