Brief Title
Pembrolizumab With Ataluren in Patients With Metastatic pMMR and dMMR Colorectal Carcinoma or Metastatic dMMR Endometrial Carcinoma: the ATAPEMBRO Study
Official Title
Study of Pembrolizumab Combined With Ataluren In Patients With Metastatic pMMR and dMMR Colorectal Adenocarcinomas or Metastatic dMMR Endometrial Carcinoma: the ATAPEMBRO Study
Brief Summary
Single Center, open label, Phase I-II trial designed to test the safety and efficacy of the
combination of Ataluren and Pembrolizumab for the treatment of metastatic mismatch repair
deficient and proficient colorectal adenocarcinoma and metastatic mismatch repair deficient
endometrial carcinoma.
Detailed Description
In controlling tumor outgrowth an intact immune surveillance is very important. PD-1
receptor-ligand interaction is a major pathway hijacked by tumors to suppress this immune
control.
Pembrolizumab is a potent and highly selective humanized monoclonal antibody designed to
directly block the interaction between PD-1 and its ligands and is registered for the
treatment of advanced (unresectable or metastatic) melanoma of locally advanced or metastatic
NSCLC in adults. In an earlier study it's effect has been shown in mismatch repair deficient
tumors.
Ataluren is designed to allow the protein making apparatus (the ribosome) in cells to skip
over a premature stop codon (PTC), allowing the cells to translate the sequence downstream of
a premature termination codon (PTC) in mRNA transcripts. This may result in the translation
of additional out-of-frame code, which is available in abundance in dMMR tumors. We argue
that this may result in new target peptides for the immune-system to recognize cancer cells.
The investigators hypothesize that the formation of these peptides by Ataluren can enhance
the effect of Pembrolizumab anti-PD1 therapy.
Therefore the investigators designed a Single Center, open label, Phase I-II trial designed
to test the safety and efficacy of the combination of Ataluren and Pembrolizumab for the
treatment of metastatic mismatch repair deficient and proficient colorectal adenocarcinoma
and metastatic mismatch repair deficient endometrial carcinoma.
Study Phase
Phase 1/Phase 2
Study Type
Interventional
Primary Outcome
Incidence of treatment-Emergent Adverse Event and the determination of the maximum tolerable dose of Ataluren.
Secondary Outcome
Immune-related progression free survival
Condition
Colorectal Cancer
Intervention
Ataluren + Pembrolizumab
Study Arms / Comparison Groups
Phase I dMMR and pMMR
Description: 2-4 groups of 3 patients treatment with 200mg i.v. Pembrolizumab q3w and dose escalation of Ataluren in order to determine the Ataluren MTD. These patients can either be pMMR/dMMR CRC and dMMR EC patients.
Publications
* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.
Recruitment Information
Recruitment Status
Drug
Estimated Enrollment
47
Start Date
August 1, 2019
Completion Date
August 1, 2023
Primary Completion Date
August 1, 2021
Eligibility Criteria
In order to be eligible for participation in this trial, the subject must:
- Have at least one lesion with measurable disease as defined by 10mm in longest
diameter for a soft tissue lesions or 15mm in short axis for a lymph node by RECIST
1.1 and irRC criteria for response assessment.
- Have received at least 1 prior cancer therapy regimen for metastatic CRC, or have
refused palliative chemotherapy. In the latter case this should have been documented.
- Have a life expectancy of greater than 3 months.
- Have normal organ and marrow function as defined in protocol
- Be willing and able to provide written informed consent/assent for the trial.
- Be at least 18 years of age on day of signing informed consent.
- Be willing to provide tissue from a newly obtained pre-treatment core or excisional
biopsy of a metastatic tumor lesion and the primary tumor lesion (when in place).
Subjects for whom newly-obtained samples cannot be provided (e.g. inaccessible by
colonoscopy or CT-guided approaches or due to safety concerns) may submit an archived
specimen only upon agreement from the Sponsor.
- Be willing to provide tissue post-treatment of a core or excisional biopsy of a
metastatic tumor lesion (when still in place) or of the primary tumor (when in place).
- Have a performance status of 0 or 1 on the ECOG Performance Scale.
- Female subject of childbearing potential should have a negative urine or serum
pregnancy within 72 hours prior to receiving the first dose of study medication. If
the urine test is positive or cannot be confirmed as negative, a serum pregnancy test
will be required.
- Male subjects of childbearing potential (Section 4.7.2) must agree to use an adequate
method of contraception as outlined in Section 4.7.2- Contraception, starting with the
first dose of study therapy through 120 days after the last dose of study therapy.
Subject must be excluded from participating in the trial if the subject:
- Has known active central nervous system (CNS) metastases and/or carcinomatous
meningitis. Subjects with previously treated brain metastases may participate provided
they are stable (without evidence of progression by imaging for at least four weeks
prior to the first dose of trial treatment and any neurologic symptoms have returned
to baseline), have no evidence of new or enlarging brain metastases, and are not using
steroids for at least 1 week prior to trial treatment.
- Has a history of prior treatment with anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137,
anti-OX-40, anti-CD40, or anti-CTLA-4 antibodies.
- Has received growth factors including, but not limited to, granulocyte-colony
stimulating factor (G-CSF), granulocyte macrophage-colony stimulating factor (GM-CSF),
erythropoietin, etc. within 2 weeks of study drug administration. Use of such agents
while on study is also prohibited. Prior use of growth factors should be documented in
the patient's medical history.
- Has an uncontrolled intercurrent illness including, but not limited to, ongoing or
active infection, symptomatic congestive heart failure, unstable angina pectoris,
cardiac arrhythmia, or psychiatric illness/social situations that would limit
compliance with study requirements.
- Has a history of any autoimmune disease: Patients with a history of inflammatory bowel
disease, including ulcerative colitis and Crohn's Disease, are excluded from this
study, as are patients with a history of symptomatic disease (e.g., rheumatoid
arthritis, systemic progressive sclerosis [scleroderma], systemic lupus erythematosus,
autoimmune vasculitis [e.g., Wegener's Granulomatosis]); CNS or motor neuropathy
considered of autoimmune origin (e.g., Guillain-Barre Syndrome and Myasthenia Gravis,
multiple sclerosis). Patients with thyroid disease will be allowed. Autoimmune
diagnoses not listed here must be approved by the protocol chair.
- Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any
other form of immunosuppressive therapy within 7 days prior to the first dose of trial
treatment.
- Has a known history of active TB (Bacillus Tuberculosis)
- Hypersensitivity to pembrolizumab or ataluren or any of their excipients.
- Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study
Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events
due to agents administered more than 4 weeks earlier.
- Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy
within 2 weeks prior to study day 1 or who has not recovered (i.e., ≤ Grade 1 or at
baseline) from adverse events due to a previously administered agent.
- Has a known additional malignancy that is progressing or requires active treatment.
Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the
skin that has undergone potentially curative therapy or in situ cervical cancer.
- Has active autoimmune disease that has required systemic treatment in the past 2 years
(i.e. with use of disease modifying agents, corticosteroids or immunosuppressive
drugs). Replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid
replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a
form of systemic treatment.
- Has known history of, or any evidence of active, non-infectious pneumonitis.
- Has an active infection requiring systemic therapy.
- Has a history or current evidence of any condition, therapy, or laboratory abnormality
that might confound the results of the trial, interfere with the subject's
participation for the full duration of the trial, or is not in the best interest of
the subject to participate, in the opinion of the treating investigator.
- Has known psychiatric or substance abuse disorders that would interfere with
cooperation with the requirements of the trial.
- Is pregnant or breastfeeding, or expecting to conceive or father children within the
projected duration of the trial, starting with the pre-screening or screening visit
through 120 days after the last dose of trial treatment.
- Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
- Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA
[qualitative] is detected).
- Has received a live vaccine within 30 days of planned start of study therapy.
- Has received amino glucoside antibiotics within 3 days of planned start of study
therapy
Gender
All
Ages
18 Years - N/A
Accepts Healthy Volunteers
No
Contacts
Punt, Prof., 0031205662339, [email protected]
Location Countries
Netherlands
Location Countries
Netherlands
Administrative Informations
NCT ID
NCT04014530
Organization ID
NL64152.018.18
Secondary IDs
2017-004752-34
Responsible Party
Principal Investigator
Study Sponsor
Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
Collaborators
Merck Sharp & Dohme Corp.
Study Sponsor
Punt, Prof., Study Director, Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
Verification Date
January 2020