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Mucinous Adenocarcinoma of the ColonPhase 2NCT02235324

Ziv-Aflibercept Followed by Ziv-Aflibercept, Fluorouracil, and Leucovorin Calcium in Treating Patients With Stage IV Colorectal Cancer

A Phase 2 study testing ziv-aflibercept, leucovorin calcium and fluorouracil in people with Mucinous Adenocarcinoma of the Colon and Mucinous Adenocarcinoma of the Rectum, run by University of Southern California at 1 site in United States.

Withdrawn

Withdrawn. The study stopped before anyone enrolled.

Official record
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Trial summary

This phase II trial studies how long it takes colorectal cancer resistant to standard treatment to grow while receiving treatment with ziv-aflibercept, and how well adding fluorouracil and leucovorin calcium to ziv-aflibercept works in treating patients with stage IV colorectal cancer after they progress on… Read more about this study

Who is it for?
Ages 18 years and older
What is being tested?
ziv-aflibercept, leucovorin calcium and fluorouracil
Type of treatment
Injection or infusion
Could I receive a placebo?
No, everyone receives an active treatment
How many people
0 participants
Where
1 siteUnited States
Study dates
Mar 2015to Mar 2018
Phase
Phase 2
Are there results?
None posted in the registry

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

  • Histologically confirmed stage IV colorectal adenocarcinoma previously treated with FOLFOX and FOLFIRI and bevacizumab, receipt of cetuximab or panitumumab is not required, and has shown progression or intolerant of both oxaliplatin and irinotecan-based regimens; baseline tumor assessments must be done within 28 days of starting treatment
  • Patients must have lesions that can be easily biopsied
  • Representative tumor tissue specimens (paraffin block preferred)
  • Signed informed consent prior to initiation of any study-specific procedure or treatment, including agreement to two biopsies during the study
  • Eastern Cooperative Oncology Group (ECOG) performance status of 0-2
  • Able to comply with the protocol, including tissue and blood sampling
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  • Leukocytes >= 3,000 per mm^3
  • Absolute neutrophil count >= 1,000 per mm^3
  • Platelet count >= 75,000 per mm^3
  • Hemoglobin >= 9 g/dL (may be transfused to maintain or exceed this level)
  • Creatinine clearance according to the Cockcroft and Gault formula of >= 50 mL/min
  • Urine for proteinuria should be < 2 +; patients discovered to have >= 2 + proteinuria on dipstick urinalysis at baseline should undergo a 24-hour urine collection and must demonstrate < 1 g of protein in 24 hours
  • Total bilirubin < 1.5 x upper limit of normal (ULN)
  • Aspartate aminotransferase and alanine aminotransferase < 2.5 x ULN
  • International normalized ratio =< 1.5 and activated prothrombin time =< 1.5 x ULN for patients not receiving anti-coagulation therapy
  • The use of full-dose oral or parenteral anticoagulants is permitted as long as the international normalized ratio (INR) or activated partial thromboplastin time (aPTT) is within therapeutic limits (according to the medical standard of the enrolling institution), and the patient has been on a stable dose of anticoagulants for at least two weeks prior to the first study treatment
  • Female patients should not be pregnant or breast-feeding
  • A female of child-bearing potential is any woman (regardless of sexual orientation, having undergone a tubal ligation, or remaining celibate by choice) who meets the following criteria:
  • Has not undergone hysterectomy or bilateral oophorectomy; OR
  • Has not been naturally postmenopausal for at least 12 consecutive months (i.e. has had menses at any time in the preceding 12 months)
  • Female patients with childbearing potential should agree to use effective, non-hormonal means of contraception (intrauterine contraceptive device, barrier method of contraception in conjunction with spermicidal jelly or surgically sterile) during the study and for a period of at least 6 months following the last administration of study drug
  • Female patients with an intact uterus (unless amenorrheic for the last 24 months) must have a negative serum pregnancy test within 7 days prior to randomization into the study
  • Male patients must agree to use effective contraception during the study and for a period of at least 6 months following the last administration of study drugs, even if they have been surgically sterilized

Who cannot join

  • Any prior systemic treatment with targeted antiangiogenic agents except for bevacizumab; receipt of cetuximab or panitumumab is not an exclusion criteria
  • Radiotherapy to any site for any reason within 14 days prior to treatment
  • Uncontrolled intercurrent illness including, but not limited to
  • Any of the following within 6 months prior to inclusion: myocardial infarction, severe/unstable angina pectoris, coronary/peripheral artery bypass graft, New York Heart Association (NYHA) class III or IV congestive heart failure, stroke or transient ischemic attack
  • Any of the following within 3 months prior to inclusion: grade 3-4 gastrointestinal bleeding/hemorrhage (unless due to resected tumor), treatment resistant peptic ulcer disease, erosive esophagitis or gastritis, infectious or inflammatory bowel disease, diverticulitis, pulmonary embolism or other uncontrolled thromboembolic event
  • History of allergic reactions attributed to compounds of similar chemical or biologic composition to agents used in the study
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  • History of arterial thromboembolic events
  • History of abdominal fistula formation, gastrointestinal perforation, or abdominal abscess within six months
  • History or evidence of inherited bleeding diathesis or coagulopathy with a risk of bleeding
  • Patients must not be pregnant or nursing
  • Major surgical procedure, open biopsy, or significant traumatic injury within 28 days before start of study drug
  • Any hemorrhage or bleeding event >= CTCAE grade 3 within 4 weeks prior to the start of study medication
  • Non-healing wound, ulcer, or bone fracture
  • Inadequately controlled hypertension (systolic blood pressure [SBP] > 150 mmHg, diastolic blood pressure [DBP] > 100 mg Hg)
  • Known positivity for human immunodeficiency virus (HIV)
  • Malignancies other than colorectal adenocarcinoma within 5 years prior to treatment, except for adequately treated carcinoma in situ of the cervix, basal or squamous cell skin cancer, localized prostate cancer treated surgically with curative intent, and ductal carcinoma in situ treated surgically with curative intent
  • Clinically detectable (by physical exam) third-space fluid collections (e.g. ascites or pleural effusion) that cannot be controlled by drainage or other procedures prior to study entry
  • Treatment with any other investigational agent, or participation in another investigational drug trial within 28 days prior to randomization
  • Patients can withdraw consent anytime during the study

Trial locations and contacts

1 site in 1 country.

United States1 site

  • USC Norris Comprehensive Cancer Center

    Los Angeles, California, 90089

Other trials in United States

About this study

Official title: Phase II Study of Ziv-Aflibercept Followed by the Addition of 5-FU in the Third Line Setting of Metastatic Colorectal Cancer

This phase II trial studies how long it takes colorectal cancer resistant to standard treatment to grow while receiving treatment with ziv-aflibercept, and how well adding fluorouracil and leucovorin calcium to ziv-aflibercept works in treating patients with stage IV colorectal cancer after they progress on ziv-aflibercept alone. Ziv-aflibercept may stop the growth of colorectal cancer by blocking the formation of tumor blood vessels. Fluorouracil and leucovorin calcium are drugs used in chemotherapy. Fluorouracil works to stop the growth of tumors cells by preventing the cells from growing and dividing. Leucovorin calcium helps fluorouracil work better. Adding fluorouracil and leucovorin calcium to ziv-aflibercept may be an effective treatment for patients who progress on ziv-aflibercept alone.

Read the detailed description

PRIMARY OBJECTIVES:

  1. To determine the progression-free survival during the first phase of the study (PFS1) in patients with metastatic colorectal cancer treated with single agent ziv-aflibercept after progressing on leucovorin calcium, fluorouracil, oxaliplatin (FOLFOX) and leucovorin calcium, fluorouracil, irinotecan hydrochloride (FOLFIRI) with bevacizumab +/- cetuximab or panitumumab.

II. To determine the progression-free survival (PFS2) in patients with metastatic colorectal cancer treated with ziv-aflibercept and 5-fluorouracil (fluorouracil), after progressing on ziv-aflibercept alone.

SECONDARY OBJECTIVES:

  1. Overall survival. II. Response rate. III. Incidence and nature of adverse events. IV. Growth modulation index (ratio of PFS2/PFS1).

TERTIARY OBJECTIVES:

  1. To determine relevant biomarkers which can distinguish patients with a progression free survival greater than 3 months on single agent ziv-aflibercept (tumor vascular endothelial growth factor [VEGF], vascular endothelial growth factor receptor [VEGFR]1 and 2, baseline plasma phosphatidylinositol glycan anchor biosynthesis, class F [PlGF]).

II. Plasma levels of VEGF-A, B, C, D, intercellular adhesion molecule 1 (ICAM), chemokine (C-X-C motif) ligand 1 (melanoma growth stimulating activity, alpha) (Gro alpha), hepatocyte growth factor (HGF), stem cell growth factor beta (SCGF beta) prior to treatment and with each cycle of therapy.

III. Single nucleotide polymorphisms (SNPs) of VEGFA, VEGFR1 \& 2 \& 3, interleukin (IL)8, angiopoietin-2 (Ang2), IL-6, ICAM, PlGF, neuropilin (NRP)1 \& 2, chemokine (C-X-C motif) receptor 2 (CXCR2) and others in the angiogenic pathway.

IV. Tumor messenger ribonucleic acid (mRNA) expression levels of VEGF B, C, D, VEGFR 3; NRP 1, 2, and VEGF isoforms on biopsy specimens taken at trial initiation and upon disease progression and addition of 5-FU.

  1. Correlation of biomarkers with toxicity of ziv-aflibercept alone and with 5-FU.

OUTLINE:

PHASE I: Patients receive ziv-aflibercept intravenously (IV) over 1 hour on day 1. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity. At the time of progression, patients proceed to Phase II.

PHASE II: Patients receive ziv-aflibercept IV over 1 hour, leucovorin calcium IV over 1 minute, and fluorouracil IV over 46 hours on day 1. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months.

Being tested
ziv-aflibercept, leucovorin calcium, fluorouracil, laboratory biomarker analysis
Medical subject headings
Colonic Neoplasms, Rectal Neoplasms

What participants receive

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

  • ziv-afliberceptBiological

    Also called aflibercept, vascular endothelial growth factor trap, VEGF Trap, Zaltrap

    Given IV

  • leucovorin calciumDrug

    Also called CF, CFR, LV

    Given IV

  • fluorouracilDrug

    Also called 5-fluorouracil, 5-Fluracil, 5-FU

    Given IV

  • laboratory biomarker analysisOther

    Correlative studies

Study groups in NCT02235324
Study groupRoleWhat they receive
Treatment (ziv-aflibercept, leucovorin calcium, fluorouracil)ExperimentalPHASE I: Patients receive ziv-aflibercept IV over 1 hour on day 1. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity. At the time of progression, patients proceed to Phase II. PHASE II: Patients receive ziv-aflibercept IV over 1 hour, leucovorin calcium IV over 1 minute, and fluorouracil IV over 46 hours on day 1. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity.
Receives: Biological: ziv-aflibercept; Drug: leucovorin calcium; Drug: fluorouracil; Other: laboratory biomarker analysis

What is being measured

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

  1. Progression-free survival during the first phase of the study

    Point and precision estimates, median and its 95% confidence interval (CI) will be provided. To examine associations between biomarkers and PFS1, the difference in progression-free survival by each biomarker level will be detected.

    Measured: Period from the start of ziv-aflibercept to the date of radiographic or clinical progression, death, or within 30 days off treatment

  2. Progression-free survival during the second phase of the study

    Using the Simon's 2-stage optimum design, there is a 90% power to detect improvement of adding fluorouracil to ziv-aflibercept on PFS2 and the type I error rate is 2.3%. Point and precision estimates, median and its 95% CI will be provided.

    Measured: Period from the start of fluorouracil with ziv-aflibercept to the date of radiographic or clinical progression, death, or within 30 days off treatment

Secondary outcomes (3)

  1. Overall survival (OS)

    OS will be summarized with Kaplan-Meyer plots to describe the outcome of patients treated on this protocol.

    Measured: Period from treatment initiation with single agent ziv-aflibercept to death, assessed up to 3 years

  2. Response rate assessed using Response Evaluation Criteria in Solid Tumors 1.1

    Response rates will be calculated as the percent of evaluable patients whose best response is a complete response or partial response, and exact 95% confidence intervals will be calculated for this estimate.

    Measured: Up to 3 years

  3. Incidence of adverse events graded according to NCI CTCAE version 4.0

    Toxicities observed at each leg of the study will be summarized in terms of type (organ affected, laboratory determination), severity (by NCI Common Toxicity Criteria and nadir or maximum values for the laboratory measures), time of onset, duration, and reversibility or outcome. Tables will be created to summarize these toxicities and side effects by leg and by course of therapy.

    Measured: Within 30 days of the last administration of the study drug

Timeline

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

  1. First posted9 Sep 2014 (estimated)
  2. Study startMar 2015
  3. Primary completionMar 2017 (estimated)
  4. Study completionMar 2018 (estimated)

Why it stopped: Lack of funding

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 2
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
0 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT02235324
Sponsor's protocol ID
3C-13-7
Other IDs
NCI-2014-01806, HS-14-00081, 3C-13-7, P30CA014089
Status last verified
May 2015
First submitted
4 Sep 2014
Last updated
6 May 2015
Results posted
No
Data monitoring committee
Yes

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing ziv-aflibercept, leucovorin calcium and fluorouracil in people with Mucinous Adenocarcinoma of the Colon and Mucinous Adenocarcinoma of the Rectum, run by University of Southern California at 1 site 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 23 inclusion and 19 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: withdrawn, as of the sponsor's last update on 6 May 2015. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site 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 phase mean?

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?

The study was withdrawn before enrolling participants, so there are no results.

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?

Progression-free survival during the first phase of the study (time frame: Period from the start of ziv-aflibercept to the date of radiographic or clinical progression, death, or within 30 days off treatment). 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 NCT02235324.

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 6 May 2015.

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