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Gastrointestinal CancerPhase 1/2MEKiAUTONCT04214418

Study of Combination Therapy With the MEK Inhibitor, Cobimetinib, Immune Checkpoint Blockade, Atezolizumab, and the AUTOphagy Inhibitor, Hydroxychloroquine in KRAS-mutated Advanced Malignancies

A Phase 1/2 study testing Cobimetinib, Hydroxychloroquine and Atezolizumab in people with Gastrointestinal Cancer, run by Columbia University at 2 sites in United States.

Terminated

Stopped early. The study ended before it was planned to and will not resume.

Official record
Search all trials

Trial summary

This research study is for patients with an advanced cancer that carries a mutation in a gene called KRAS. Genes are parts of our DNA which carry instructions for a cell (the smallest component of an body part). In many cancers, the KRAS gene contains errors (mutations) which allows the tumors to grow. Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Gastrointestinal Cancer
What is being tested?
Cobimetinib, Hydroxychloroquine and Atezolizumab
Could I receive a placebo?
No, everyone receives an active treatment
How many people
27 participants
Where
2 sitesUnited States
Study dates
12 Feb 2020to 1 Jul 2022
Phase
Phase 1/2
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Histological or pathological confirmation of malignancy with a KRAS-activating mutation.
  • Extent of disease Advanced disease for which no curable options are available. Subjects who are not deemed candidates for these curative therapies will be eligible if they meet other criteria.
  • Prior treatments
  • Pancreatic adenocarcinoma Subjects must have progressed on or be intolerant of combination therapy containing either 5-Fluorouracil/Capecitabine- and/or gemcitabine-based therapy. Subjects who experienced disease recurrence while receiving adjuvant chemotherapy or within three months of completing adjuvant chemotherapy are eligible.
  • Colorectal adenocarcinoma Subjects must have progressed on or be intolerant of combination therapy containing 5-Fluorouracil/Capecitabine, and must have received Oxaliplatin and Irinotecan.
  • MSI-H/dMMR or NTRK-fusion positive tumors Subjects must have received prior treatment with approved drugs for tumors harboring these aberrations.
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  • Histology agnostic cancers other than pancreatic and colorectal adenocarcinoma (see above; Phase 1 and 2) Subjects must have progressed on or be intolerant of all standard of care therapies that result in a median progression free survival benefit of ≥ 8 weeks, or overall response rate of >5%.
  • Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
  • Age ≥18 years
  • Adequate hematological and end-organ function (test results from within 14 days prior to initiation of study treatment):
  • Absolute neutrophil count (ANC) ≥ 1.5 x 109/L without granulocyte colony-stimulating factor support
  • White blood cell (WBC) count ≥ 2.5 x 109/L
  • Lymphocyte count ≥ 0.5 x 109/L
  • Platelet count ≥ 100 x 109/L without transfusion
  • Hemoglobin (Hgb) > 9.0 g/dL
  • Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP) ≤ 2.5 x upper limit of normal (ULN), unless elevated secondary to bilary obstruction from the pancreas mass and amenable to decompression prior to initiation of therapy
  • Serum total bilirubin ≤ 1.5 x ULN, unless in patients with known Gilbert disease (≤ 3 x ULN), or unless elevated secondary to bilary obstruction from the pancreas mass and amenable to decompression prior to administration of investigational therapy
  • Albumin ≥ 3.0g/dL
  • Creatinine within ULN or calculated creatinine clearance (CrCl) >50 mL/min using the Cockcroft-Gault formula
  • International Normalized Ratio (INR) and activated partial thromboplastin time (aPTT) ≤ 1.5 x ULN except for those who are on stable anticoagulation for at least three months.
  • Measurable disease according to Immune-modified Response Evaluation Criteria in Solid Tumors (IM-RECIST) and tumor accessible for fresh biopsy if ten adequate paired biopsied specimens have not been procured (Phase 1)
  • Negative pregnancy test and agree to effective form of contraception.
  • Birth control agreement Fertile men must agree to use an effective method of birth control during the study and for up to 3 months after the last dose of study drug.
  • Informed consent Participants must be willing and able to provide written informed consent prior to any study-related procedures and to comply with all study requirements.
  • Ability to comply Participants must be able to comply with the study protocol, according to the investigator's judgement.
  • Deep venous thrombosis (DVT) testing Participants must have undergone lower extremity dopplers to rule out DVT within the screening period, and undergo therapeutic anticoagulation if evidence of DVT is identified.
  • Venous thromboembolism (VTE) testing Patients deemed at increased risk of VTE based on primary cancer, which includes pancreatic adenocarcinoma, gastric/gastroesophageal junction adenocarcinoma, or central nervous system (CNS) malignancy, are to undergo prophylaxis anticoagulation with enoxaparin. Subjects who are unable to receive enoxaparin ,but deemed at increased risk of VTE will not be eligible and consultation with the Principal Investigator is required.
  • Anticoagulation treatment Subjects who are stable on full-dose anticoagulation medication for at least 8 weeks are considered eligible. However, subjects who have an increased clot burden on full-dose anticoagulation will be considered eligible only with the approval of the Principal Investigator.

Who cannot join

  • Prior treatment with investigational therapy. Participants may not have had any treatments with investigational therapy within the 28 days prior to initiation of study treatment.
  • Prior radiation therapy Participants may not have had radiation therapy within 2 weeks prior to initiation of study treatment. Participants may not have had previous radiotherapy to 25% or more of the bone marrow.
  • Prior Therapy Participants may not have had systemic chemotherapy within 14 days or 5 half-lives of the drug (whichever is longer) prior to initiation of study treatment.
  • In addition, the following prior treatment is not allowed during Phase 1 of the study:
  • Receptor tyrosine kinase inhibitors targeting MAP kinase pathway;
  • Any pharmacological agents inhibiting the autophagy pathway.
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  • In addition, the following prior treatment is not allowed during Phase 2 of the study:
  • T-cell co-stimulating agents or immune checkpoint blockade therapies
  • Receptor tyrosine kinase inhibitors targeting Mitogen-Activated Protein (MAP) kinase pathway;
  • Any pharmacological agents inhibiting the autophagy pathway.
  • Adverse events from prior anti-cancer therapy Participants may not initiate treatment if they have adverse events from prior anti-cancer therapy that have not resolved to Grade ≤ 1 or better, with the exception of Grade ≤ 2 peripheral neuropathy or any grade alopecia.
  • Patients currently receiving any other investigational agents
  • Concomitant treatment with other anti-neoplastic agents (hormone therapy acceptable)
  • Uncontrolled pleural effusion, pericardial effusion, or ascites
  • Patients with symptomatic brain metastases Subjects with untreated brain metastasis ≤ 1 cm can be considered eligible if deemed asymptomatic by the investigator upon consultation with the medical monitor, and do not require immediate radiation or steroids. Subjects with brain metastasis that is treated and stable for 1 month may be considered eligible if they are asymptomatic and on stable dose of steroids, or if they do not require steroids following successful local therapy.
  • Uncontrolled hypercalcemia or symptomatic hypercalcemia requiring continued use of bisphosphonate therapy.
  • Recent major surgery or significant traumatic injury Participants may not have undergone major surgery or experienced significant traumatic injury within 14 days prior to initiating study treatment, or be recovering from a procedure related to adverse events of ≤ Grade 1.
  • Active or history of autoimmune disease or immune deficiency
  • With the following exceptions:
  • Patients with a history of autoimmune-related hypothyroidism who are on stable thyroid-replacement hormone are eligible for the study.
  • Patients with controlled Type 1 diabetes mellitus who are on a stable insulin regimen are eligible for the study.
  • Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic manifestations only are eligible for the study provided all of following conditions are met:
  • Rash must cover <10% of body surface area;
  • Disease is well-controlled at baseline and requires only low-potency topical corticosteroids;
  • No occurrence of acute exacerbations of the underlying condition requiring psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologic agents, oral calcineurin inhibitors, or high-potency or oral corticosteroids within the previous 12 months.
  • History of idiopathic pulmonary fibrosis, interstitial lung disease, organizing pneumonia, drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on screening chest computed tomography scan [history of radiation pneumonitis in the radiation field (fibrosis) is permitted].
  • Positive for HIV at screening or any time prior to screening Patients without prior positive HIV test result will undergo an HIV test at screening, unless not permitted under local regulations.
  • Active Hepatitis B virus (HBV) infection (chronic or acute) Defined as having a positive hepatitis B surface antigen (HBsAg) test at screening. Patients with a past or resolved HBV infection, defined as having a negative HBsAg test and a positive total hepatitis B core antibody test at screening, are eligible for the study.
  • Active hepatitis C virus (HCV) infection Defined as positive HCV antibody test followed by a positive HCV RNA test at screening. The HCV RNA test will be performed only for patients who have a positive HCV antibody test.
  • Known clinically significant liver disease
  • Active tuberculosis
  • Severe infection Patients may not have had a severe infection within 4 weeks prior to initiation of study treatment. This includes, but is not limited to, hospitalization for complications of infection, bacteremia, or severe pneumonia. However, patients who were admitted for biliary tract infection due to bile duct obstruction at time of diagnosis must have a functioning biliary stent (as evidenced by declining total bilirubin and ≤ 2 x ULN) and resolved infection (defined by normalization of elevated white blood cell count, absence of signs of infection) and completion of an antibiotic course (at least a seven-day course) prior to initiation of therapy.
  • Recent antibiotic treatment Patients may not have been treated with therapeutic oral or intravenous (IV) antibiotics within 2 weeks prior to initiation of study treatment, except for biliary tract infection due to bile duct obstruction from the pancreas mass. Patients receiving prophylactic antibiotics are eligible for the study.
  • Significant cardiovascular disease Patient may not have significant cardiovascular disease within 12 months prior to initiation of study treatment, seizure disorder, uncontrolled hypertension, or unstable arrhythmia or unstable angina within 3 months prior to initiation of study treatment.
  • Left ventricular ejection fraction below institutional lower limit of normal or below 50%, whichever is lower
  • Baseline QTcF ≥ 450 ms (males) or ≥ 470 ms (females)
  • Grade ≥ 3 hemorrhage or bleeding event within 28 days prior to initiation of study treatment
  • Prior autologous stem cell, allogeneic stem cell, or solid organ transplantation
  • History of malignancy Patient may not have a history of malignancy other than PDA within 2 years prior to screening, with the exception of those with a negligible risk of metastasis or death.
  • Recent vaccination Patients may not have been treated with a live, attenuated vaccine within 4 weeks prior to initiation of study treatment, or anticipate the need for such a vaccine during treatment with atezolizumab or within 5 months after the last dose of atezolizumab.
  • History of severe allergic anaphylactic reactions to chimeric or humanized antibodies or fusion proteins
  • Known allergy or hypersensitivity to 4-aminoquinoline compounds or any of the study drug excipients
  • Recent immunosuppressive treatment
  • Patients may not have been treated with systemic immunosuppressive medication within 2 weeks prior to initiation of study treatment, or anticipate the need for systemic immunosuppressive medication during the course of the study, with the following exceptions:
  • Patients who received mineralocorticoids, corticosteroids for chronic obstructive pulmonary disease or asthma, or low-dose corticosteroids for orthostatic hypotension or adrenal insufficiency are eligible for the study if receiving equivalent to < 10mg of prednisone daily.
  • Patients who received a one-time pulse dose of systemic immunosuppressant medication are eligible for the study after approval from the Principal Investigator.
  • Inability to swallow medication or malabsorption condition that would alter the absorption of orally administered medications
  • History of retinal pathology
  • Specifically, patients will be excluded from study participation if they currently are known to have any risk factors for retinal vein occlusion (RVO), including:
  • Glaucoma with intraocular pressure ≥ 21 mmHg;
  • Grade ≥ 2 serum cholesterol;
  • Grade ≥ 2 hypertriglyceridemia;
  • Grade ≥ 2 uncontrolled hypertension (patients with a history of hypertension controlled with anti-hypertensive medication to Grade ≤ 1 are eligible).
  • Pregnancy and breastfeeding
  • Other contraindicated conditions (opinion of treating investigator)
  • Concomitant strong CYP3A4 inhibitors and inducers Concomitant treatment is permitted if the medication is not expected to interfere with the evaluation of safety or efficacy of the study drug.
  • Uncontrolled psoriasis, porphyria, proximal myopathy or neuropathy
  • Severe depression Subjects hospitalized for depression within the past 2 years, or who have prior suicidal attempts will be excluded.
  • Glucose-6-phosphate dehydrogenase deficiency
  • History of connective tissue disorders
  • Subjects on greater than once daily dose of antacid therapy
  • Concomitant use of any of the following drugs:
  • Digoxin
  • Pharmacological agents known to prolong QT interval
  • Mefloquine or other agents which may lower the convulsive threshold
  • Antiepileptics
  • Methotrexate
  • Cyclosporine
  • Ampicillin
  • Cimetidine

Trial locations and contacts

2 sites in 1 country.

United States2 sites

  • Columbia University Irving Medical Center

    New York, New York, 10032

  • Brown University

    Providence, Rhode Island, 02912

Other trials in United States

About this study

Official title: Phase 1/2 Open-label Study of Combination Therapy With the MEK Inhibitor, Cobimetinib, Immune Checkpoint Blockade, Atezolizumab, and the AUTOphagy Inhibitor, Hydroxychloroquine in KRAS-mutated Advanced Malignancies

This research study is for patients with an advanced cancer that carries a mutation in a gene called KRAS. Genes are parts of our DNA which carry instructions for a cell (the smallest component of an body part). In many cancers, the KRAS gene contains errors (mutations) which allows the tumors to grow. The purpose of this study is to determine if combination treatment with atezolizumab, cobimetinib, and hydroxychloroquine is safe, and if it will decrease the size of the tumor and prolong life in patients whose tumors contain this mutation. Cobimetinib and atezolizumab are both approved by the FDA for use in other cancers, but not in some cancer types being studied in this trial. Hydroxychloroquine is FDA approved to treat malaria and other conditions, but has also not been approved for these cancer types. Preliminary results have shown that this combination of drugs is effective at killing cancer cells and shrinking tumors in several KRAS-mutated cancers in animals.

Read the detailed description

The overall objective of this study is to investigate the safety and preliminary efficacy of combination therapy with cobimetinib and hydroxychloroquine, with or without atezolizumab in patients with KRAS-mutated advanced malignancies. Given that the pre-clinical and clinical benefit from this combination is from within poorly differentiated endocrine carcinoma (PDAC) animal models and human subjects with PDAC and duodenal cancer, we will include at least 12 of the 18 evaluable subjects from PDAC and/or colorectal malignancies. The phase 2 portion of the study will be amended after preliminary safety and efficacy results from phase 1 and other ongoing clinical trials have been analyzed and a summary incorporated within the protocol as an amendment including a rationale of the cohorts to be tested.

Being tested
Cobimetinib, Hydroxychloroquine, Atezolizumab
Medical subject headings
Gastrointestinal Neoplasms

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • CobimetinibDrug

    (40-60 mg) orally once daily (morning) on days 1-21 of each 28-day selective small molecule inhibitor for MEK1 and MEK2

  • HydroxychloroquineDrug

    (600mg) orally twice daily on days 1-28 of each 28-day cycle

  • AtezolizumabDrug

    Also called TECENTRIQ, MPDL3280A

    840 mg IV on Days 1 and 15 of each cycle humanized IgG1 monoclonal antibody (MAb)

Study groups in NCT04214418
Study groupRoleWhat they receive
Phase 1: Maximum Tolerated Dose (MTD)ExperimentalSubjects will be treated with combination therapy at the designated dose levels: Dose 1 - Hydroxychloroquine 600mg twice per day, Cobimetinib 40mg, no Atezolizumab Dose 2 - Hydroxychloroquine 600mg twice per day, Cobimetinib 40mg, Atezolizumab 840mg Dose 3 - Hydroxychloroquine 600mg twice per day, Cobimetinib 60mg, Atezolizumab 840mg
Receives: Drug: Cobimetinib; Drug: Hydroxychloroquine; Drug: Atezolizumab
Phase 2: Cohort 1ExperimentalAdvanced Pancreatic Adenocarcinoma (N = 23-67) subjects will receive study treatment based on the MTD determined from Phase 1
Receives: Drug: Cobimetinib; Drug: Hydroxychloroquine; Drug: Atezolizumab
Phase 2: Cohort 2ExperimentalAdvanced Colorectal Adenocarcinoma (N = 20-34) subjects will receive study treatment based on the MTD determined from Phase 1
Receives: Drug: Cobimetinib; Drug: Hydroxychloroquine; Drug: Atezolizumab
Phase 2: Cohort 3ExperimentalHistology Agnostic Adenocarcinoma (N = 23-56) subjects will receive study treatment based on the MTD determined from Phase 1
Receives: Drug: Cobimetinib; Drug: Hydroxychloroquine; Drug: Atezolizumab

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Phase 1: Estimated Maximum Tolerated Dose (MTD) Hydroxychloroquine (HCQ)

    The MTD is defined as the dose combination at which 30% of the patients experience a dose-limiting toxicity (DLT) by the end of Cycle 2

    Measured: 28 days

  2. Phase 1: Estimated Maximum Tolerated Dose (MTD) Cobimetinib

    The MTD is defined as the dose combination at which 30% of the patients experience a dose-limiting toxicity (DLT) by the end of Cycle 2

    Measured: 28 days

Secondary outcomes (1)

  1. Phase 1: Number of Participants With Treatment-Emergent Adverse Events

    Adverse events (AEs) and serious adverse events (SAEs) that are deemed to be related to treatment

    Measured: Up to 20 weeks

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted2 Jan 2020
  2. Study start12 Feb 2020
  3. Primary completion11 Apr 2022
  4. Study completion1 Jul 2022

Why it stopped: Toxicity and Lack of Efficacy

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1/2
Primary purpose
Treatment
Allocation
Non-randomised
Intervention model
Sequential
Model description
The phase 1 portion of the study will be conducted using the time-to-event continue reassessment method (TITE-CRM) using four dose levels. The phase 2 portion of the study will use the recommended phase 2 dose for three cohorts with KRAS mutation - 1. Pancreatic adenocarcinoma; 2. Colorectal adenocarcinoma; and 3. Histology agnostic adenocarcinoma.
Masking
None (open label)
Enrolment
27 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT04214418
Sponsor's protocol ID
AAAS4165
Other IDs
ML41472
Acronym
MEKiAUTO
Status last verified
Nov 2024
First submitted
27 Dec 2019
Last updated
18 Dec 2024
Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No
Individual data sharing
Yes: Data and/or specimens will be sent to the sponsor coded with the subject's unique identifier; the link between the unique identifier and the subject will be maintained by the research staff at Columbia University Medical Center (CUIMC).

Publications

  • Labadie BW, Obradovic A, Raufi AG, Wasko UN, Tomassoni L, Ge L, May M, Vij M, Li L, Ross I, Sedycius SS, Sender N, Dreher N, Wu L, Abuzaid S, Iuga A, Shah P, Wulfkuhle JD, Bates S, Wong W, Pellicciotta I, Lyashchenko AK, Safran H, Izar B, Petricoin EF, Cremers S, Tan AC, Lee S, Califano A, Olive KP, Manji GA. Targeting of MEK and Autophagy in Pancreatic Adenocarcinoma and Analysis of Treatment Sensitivity in Preclinical and Clinical Models: MEKiAUTO. JCO Precis Oncol. 2026 Jun;10(6):e2600138. doi: 10.1200/PO-26-00138. Epub 2026 Jun 12.

    PubMed 42284543

Questions about this trial

What is this clinical trial studying?

A Phase 1/2 study testing Cobimetinib, Hydroxychloroquine and Atezolizumab in people with Gastrointestinal Cancer, run by Columbia University at 2 sites in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 28 inclusion and 70 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: stopped early, as of the sponsor's last update on 18 Dec 2024. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 2 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this combined phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 18 Dec 2024). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Phase 1: Estimated Maximum Tolerated Dose (MTD) Hydroxychloroquine (HCQ) (time frame: 28 days). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT04214418, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 18 Dec 2024.

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