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Trial of Afatinib in Combination With Weekly Paclitaxel in the Second Line Treatment

Primary Purpose

HER-2 Positive Gastric Cancer, Gastrooesophageal Cancer, Esophageal Cancer

Status

Withdrawn

Phase

Phase 2

Locations

Study Type

Interventional

Intervention

Afatinib

Paclitaxel

About this trial

This is an interventional treatment trial for HER-2 Positive Gastric Cancer focused on measuring Gastric, Gastroesophageal Junction, Gastroesophageal Cancer, Esophageal Cancer, Metastatic, HER2 amplified, Afatinib

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Histologically or cytologically confirmed adenocarcinoma or poorly differentiated carcinoma of the intrathoracic esophagus, gastrointestinal junction or stomach.
Tumor must be HER2 positive 3+ by immunohistochemistry or positive by Fluorescence in situ hybridization (FISH) analysis if 2+ by immunohistochemistry.
Received and failed at least one prior cytotoxic chemotherapy regimen for advanced disease that included trastuzumab.
Age greater than or equal to 18 years.
At least one measurable lesion as defined by modified RECIST criteria.
ECOG performance status less than or equal to 2.
Life expectancy of at least 12 weeks.
Normal organ and marrow function as defined.
Able to swallow and retain oral medication.
Left ventricular ejection fraction (LVEF) within institutional range of normal as measured by echocardiogram (ECHO).
Prior malignancy is acceptable if the subject is considered to be cured.
Ability to understand and the willingness to sign a written informed consent document.
All subjects of childbearing potential must agree to use acceptable methods of birth control (Men and Women).
Willingness to consent to the use of baseline diagnostic tumor specimen for correlative studies.

Exclusion Criteria:

Squamous cell carcinoma.
History of clinically relevant cardiovascular abnormalities within 6 months.
Baseline (less than 1 month before treatment) cardiac left ventricular function with resting ejection fraction of less than 50 percent measured by multigated blood pool imaging of the heart (MUGA scan) or echocardiogram.
Pregnant and lactating women are excluded from the study.
Significant or recent acute gastrointestinal disorders with diarrhea.
More than 2 prior cytotoxic chemotherapy regimens for relapsed or metastatic disease.
Major surgery, chemotherapy, radiation therapy or other cancer therapy within 3 weeks of treatment day 1.
Use of any investigational drug within 4 weeks.
Prior treatment with taxanes if given as full-dose chemotherapy for advanced disease.
Prior treatment with afatinib or any other HER2 inhibitor other than trastuzumab.
Front-line chemotherapy that did not contain trastuzumab.
Active central nervous system disease (CNS) metastases.
Planned concurrent anti-cancer therapy while taking investigational treatment.
Unresolved or unstable, serious toxicity from prior cancer treatment (any toxicities greater than grade 2).
Peripheral neuropathy of Grade 2 or greater
Concurrent disease or condition that would make the subject inappropriate for study participation or any serious medical disorder that would interfere with the subject's safety.
Dementia, altered mental status, or any psychiatric condition that would prohibit the understanding or rendering of informed consent.
Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to paclitaxel
Prior anthracycline therapy with a cumulative dose of doxorubicin (or equivalent) greater than or equal to 400 mg/m2
Pre-existing or current interstitial lung disease
Known Hypersensitivity to Afatinib (BIBW 2992) or the excipients of any of the trial drugs.
Patients unable to comply with the protocol.
Active hepatitis B infection, active hepatitis C infection or known human immunodeficiency virus HIV carrier.
Known or suspected active drug or alcohol abuse.
Concomitant treatment with strong inhibitors or inducers of P-glycoprotein.

Sites / Locations

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Afatinib and weekly Paclitaxel

Arm Description

In addition to the standard chemotherapy, afatinib 40 mg orally once daily will be administered starting on the first day of paclitaxel. Translational studies to assess circulating tumor cells at the start of therapy and then at several later time points, including at the time of progression. These studies will assess the correlation of circulating tumor cell numbers with radiographic response and pilot studies will also be conducted to assess HER2 expression, HER2 genomic amplification, HER2 pathway activation and secondary genetic changes in the HER2 coding sequence as well as other pathway components.

Outcomes

Primary Outcome Measures

Change of tumor burden (in centimeters) for participants during protocol therapy

Secondary Outcome Measures

Number of participants with adverse events.

Safety of BIBW 2992 will be evaluated as indicated by intensity and incidence of adverse events, graded according to US National Cancer Institute (NCI) Common Terminology for Adverse Events (CTCAE) Version 4.0. Safety endpoints include: events leading to dose reduction events leading to permanent treatment discontinuation the overall incidence and CTC criteria grade of adverse events, as well as relatedness of adverse events to treatment causes of death

Total number of circulating tumor cell (CTC) numbers.

CTC number changes from cycle 1, day 1 to cycle 2/3, day 1 will be correlated with response rate, progression-free survival as well as skin toxicity.

Clinical benefit in progression free survival.

Clinical benefit in overall survival.

ErbB2 levels benefit during therapy.

Diagnostic tumor specimens will be retrieved for all subjects participating in the protocol. These specimens will be used for confirmation of ErbB2 status as well as correlative analyses of clinical response.

Full Information

NCT ID

NCT02274012

First Posted

October 15, 2014

Last Updated

March 10, 2017

Sponsor

Columbia University

Collaborators

Boehringer Ingelheim

1. Study Identification

Unique Protocol Identification Number

NCT02274012

Brief Title

Trial of Afatinib in Combination With Weekly Paclitaxel in the Second Line Treatment

Official Title

Phase II Trial of Afatinib in Combination With Weekly Paclitaxel in the Second Line Treatment of HER2 Amplified Advanced Gastric, Gastroesophageal Junction and Esophageal Cancer

Study Type

Interventional

2. Study Status

Record Verification Date

March 2017

Overall Recruitment Status

Withdrawn

Why Stopped

Former PI left institution and had plans to continue at another institution.

Study Start Date

May 29, 2014 (Anticipated)

Primary Completion Date

August 12, 2015 (Actual)

Study Completion Date

August 12, 2015 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

Columbia University

Collaborators

Boehringer Ingelheim

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

The investigators are doing this research program to find out if the investigational drug, afatinib which is a medication known to block the function of the ErbB2 protein might help standard chemotherapy, in particular paclitaxel, work better. Afatinib (GILOTRIF) is a highly potent, irreversible inhibitor of the EGFR and HER2. On July 12, 2013 the United States Food and Drug Administration (US FDA) approved afatinib for the first-line treatment of patients with metastatic non-small cell lung cancer whose tumors had specific EGFR gene mutations (exon 19 deletions or exon 21 i.e. L858R substitution mutations) as detected by an FDA approved test. Paclitaxel is a standard, anti-cancer medicine that has been approved by the US Food and Drug Administration (FDA) for the treatment of lung cancer. The combination of Afatinib and Paclitaxel are considered investigational when used in this research program. An investigational drug is a drug that is not approved by the FDA for its indication.

Detailed Description

Standard Procedures: Subjects are offered second line chemotherapy with paclitaxel 80 mg/m2 intravenous infusion over 60 minutes on days 1, 8, and 15 of a 28-day cycle until disease progression or intolerable toxicity. Experimental Procedures: In addition to the standard chemotherapy, afatinib 40 mg orally once daily will be administered starting on the first day of paclitaxel. Translational studies to assess circulating tumor cells at the start of therapy and then at several later time points, including at the time of progression. These studies will assess the correlation of circulating tumor cell numbers with radiographic response and pilot studies will also be conducted to assess HER2 expression, HER2 genomic amplification, HER2 pathway activation and secondary genetic changes in the HER2 coding sequence as well as other pathway components.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

HER-2 Positive Gastric Cancer, Gastrooesophageal Cancer, Esophageal Cancer

Keywords

Gastric, Gastroesophageal Junction, Gastroesophageal Cancer, Esophageal Cancer, Metastatic, HER2 amplified, Afatinib

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

0 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Afatinib and weekly Paclitaxel

Arm Type

Experimental

Arm Description

Intervention Type

Drug

Intervention Name(s)

Afatinib

Other Intervention Name(s)

BIBW 2992

Intervention Description

Afatinib 40mg/PO daily will be administered in combination to standard of care paclitaxel.

Intervention Type

Drug

Intervention Name(s)

Paclitaxel

Other Intervention Name(s)

Taxol

Intervention Description

On the day of the first dose of afatinib, paclitaxel will be administered at a dose of 80 mg/m2 intravenously over 60 minutes on days 1, 8 and 15 of a 28-day cycle.

Primary Outcome Measure Information:

Title

Change of tumor burden (in centimeters) for participants during protocol therapy

Time Frame

Change from Baseline Tumor burden, measured every 8 weeks, up to approximately 4 years

Secondary Outcome Measure Information:

Title

Number of participants with adverse events.

Description

Time Frame

up to approximately 36 months

Title

Total number of circulating tumor cell (CTC) numbers.

Description

CTC number changes from cycle 1, day 1 to cycle 2/3, day 1 will be correlated with response rate, progression-free survival as well as skin toxicity.

Time Frame

up to approximately 36 months

Title

Clinical benefit in progression free survival.

Time Frame

every 3 months up to approximately 4 years

Title

Clinical benefit in overall survival.

Time Frame

every 3 months up to approximately 4 years

Title

ErbB2 levels benefit during therapy.

Description

Time Frame

up to approximately 4 years

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Histologically or cytologically confirmed adenocarcinoma or poorly differentiated carcinoma of the intrathoracic esophagus, gastrointestinal junction or stomach. Tumor must be HER2 positive 3+ by immunohistochemistry or positive by Fluorescence in situ hybridization (FISH) analysis if 2+ by immunohistochemistry. Received and failed at least one prior cytotoxic chemotherapy regimen for advanced disease that included trastuzumab. Age greater than or equal to 18 years. At least one measurable lesion as defined by modified RECIST criteria. ECOG performance status less than or equal to 2. Life expectancy of at least 12 weeks. Normal organ and marrow function as defined. Able to swallow and retain oral medication. Left ventricular ejection fraction (LVEF) within institutional range of normal as measured by echocardiogram (ECHO). Prior malignancy is acceptable if the subject is considered to be cured. Ability to understand and the willingness to sign a written informed consent document. All subjects of childbearing potential must agree to use acceptable methods of birth control (Men and Women). Willingness to consent to the use of baseline diagnostic tumor specimen for correlative studies. Exclusion Criteria: Squamous cell carcinoma. History of clinically relevant cardiovascular abnormalities within 6 months. Baseline (less than 1 month before treatment) cardiac left ventricular function with resting ejection fraction of less than 50 percent measured by multigated blood pool imaging of the heart (MUGA scan) or echocardiogram. Pregnant and lactating women are excluded from the study. Significant or recent acute gastrointestinal disorders with diarrhea. More than 2 prior cytotoxic chemotherapy regimens for relapsed or metastatic disease. Major surgery, chemotherapy, radiation therapy or other cancer therapy within 3 weeks of treatment day 1. Use of any investigational drug within 4 weeks. Prior treatment with taxanes if given as full-dose chemotherapy for advanced disease. Prior treatment with afatinib or any other HER2 inhibitor other than trastuzumab. Front-line chemotherapy that did not contain trastuzumab. Active central nervous system disease (CNS) metastases. Planned concurrent anti-cancer therapy while taking investigational treatment. Unresolved or unstable, serious toxicity from prior cancer treatment (any toxicities greater than grade 2). Peripheral neuropathy of Grade 2 or greater Concurrent disease or condition that would make the subject inappropriate for study participation or any serious medical disorder that would interfere with the subject's safety. Dementia, altered mental status, or any psychiatric condition that would prohibit the understanding or rendering of informed consent. Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to paclitaxel Prior anthracycline therapy with a cumulative dose of doxorubicin (or equivalent) greater than or equal to 400 mg/m2 Pre-existing or current interstitial lung disease Known Hypersensitivity to Afatinib (BIBW 2992) or the excipients of any of the trial drugs. Patients unable to comply with the protocol. Active hepatitis B infection, active hepatitis C infection or known human immunodeficiency virus HIV carrier. Known or suspected active drug or alcohol abuse. Concomitant treatment with strong inhibitors or inducers of P-glycoprotein.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Naiyer Rizvi, MD

Organizational Affiliation

Columbia University

Official's Role

Principal Investigator

12. IPD Sharing Statement

Plan to Share IPD

Links:

URL

http://www.hiccc.columbia.edu/clinical-trials

Description

Herbert Irving Comprehensive Cancer Center (HICCC) Clinical Trials Page

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Trial of Afatinib in Combination With Weekly Paclitaxel in the Second Line Treatment

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