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Metastatic Breast CancerPhase 1/2NCT01512199

Phase 1b/2 Study of U3-1287 in Combination With Trastuzumab Plus Paclitaxel in Newly Diagnosed Metastatic Breast Cancer (MBC)

A Phase 1/2 study testing U3-1287, Trastuzumab and Paclitaxel in people with Metastatic Breast Cancer, run by Daiichi Sankyo at 8 sites in 2 countries.

Terminated

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

Official record
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Trial summary

This is a Phase 1b/2 study. In Phase 1b portion, subjects will know the treatment they are receiving . Subjects will receive U3-1287 with trastuzumab plus paclitaxel . The phase 1b portion will determine if adding U3-1287 to trastuzumab plus paclitaxel will be safe in subjects with metastatic breast cancer. Read more about this study

Who is it for?
Ages 18 years and older, women only
Conditions the study is for
Metastatic Breast Cancer
What is being tested?
U3-1287, Trastuzumab and Paclitaxel
Type of treatment
Injection or infusion
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
29 participants
Where
8 sitesin 2 countries
Study dates
Nov 2011to 28 Jan 2015
Phase
Phase 1/2
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
  • Women only
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Subjects must satisfy all of the following criteria to be included in the study:
  • Women ≥ 18 years old.
  • Histologically or cytologically confirmed adenocarcinoma of the breast with metastatic disease and at least 1 measurable lesion per Response Evaluation Criteria in Solid Tumors (RECIST) guidelines Version 1.1.
  • Documented HER2+ disease as measured by FISH or IHC (3+). See Appendix 17.8 for documentation criteria.
  • Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1.
  • Hematological function, as follows:
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  • Absolute neutrophil count (ANC) ≥ 1.5 x 109/L
  • Platelet count >100 x 109/L
  • Hemoglobin ≥9 g/dL.
  • Renal function, as follows:
  • Calculated creatinine clearance ≥60 mL/min using the modified Cockcroft Gault equation.
  • Hepatic function, as follows:
  • AST ≤2.5 x ULN (if liver metastases are present, < 5 x ULN)
  • ALT ≤2.5 x ULN (if liver metastases are present, < 5 x ULN)
  • Alkaline phosphatase ≤ 2.0 x ULN (if bone or liver metastases are present, < 5 x ULN)
  • Bilirubin ≤1.5 x ULN.
  • Prothrombin time (PT) and partial thromboplastin time (PTT) ≤1.5 x ULN.
  • Availability of archived tumor sample or fresh tumor specimen (does not have to be provided by treatment start) to confirm HER2 status and for tumor biomarkers/mutation analysis.
  • Subjects must be postmenopausal (no menstrual period for a minimum of 12 months) or surgically sterile, or must use maximally effective birth control during the period of therapy, and be willing to use contraception for 6 months following the last investigational drug dose and have a negative urine or serum pregnancy test upon entry into this study if subject is of childbearing potential. Partners of subjects must be surgically sterile or willing to use a double barrier contraception method upon enrollment, during the course of the study, and for 6 months after last investigational drug dose received.
  • Subjects must be willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures.
  • Subjects must be competent and able to comprehend, sign, and date an IEC- or IRB-approved ICF before performance of any study specific procedures or tests.

Who cannot join

  • Subjects who meet any of the following criteria will be disqualified from entering the study:
  • Prior treatment for metastatic disease other than radiation therapy. Neoadjuvant/adjuvant therapy with paclitaxel, and/or docetaxel, and/or trastuzumab is allowed if completed more than 12 months prior to relapse/progression.
  • Clinically active brain metastases, defined as untreated symptomatic, or requiring therapy with steroids or anticonvulsants to control associated symptoms. Subjects with treated brain metastases that are no longer symptomatic and require no treatment with steroids or anticonvulsants may be included in the study if they have recovered from the acute toxic effect of radiotherapy.
  • LVEF < 50%. History of LVEF decline to < 50% on prior trastuzumab therapy.
  • Therapeutic or palliative radiation therapy or major surgery within 4 weeks before study drug treatment.
  • History of other malignancies, except adequately treated nonmelanoma skin cancer, curatively treated in situ cancer, or other solid tumors curatively treated with no evidence of disease for ≥ 5 years.
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  • Uncontrolled hypertension (diastolic blood pressure > 100 mmHg or systolic blood pressure > 140 mmHg). Use of antihypertensive medications is permissible to maintain blood pressure within the required parameters.
  • Clinically significant electrocardiogram (ECG) changes that obscure the ability to assess the RR, PR, QT, QTc and QRS intervals.
  • Subjects with left bundle branch block, atrial fibrillation and use of a cardiac pacemaker specifically will be excluded.
  • Ascites or pleural effusion requiring chronic medical intervention.
  • Pre-existing peripheral neuropathy > grade 1.
  • Myocardial infarction, symptomatic CHF (New York Heart Association > Class II), unstable angina, or unstable cardiac arrhythmia requiring medication within 1 year before enrollment.
  • Use of cytochrome P450 (CYP) 3A4 (CYP3A4) or CYP2C8 inducers within 28 days prior to Day 1, use of CYP3A4 or CYP2C8 inhibitors within 14 days prior to Day 1, or concurrent use of CYP3A4 or CYP2C8 inducers or inhibitors (see Appendix 17.6 for list of CYP34A and CYP2C8 inhibitors and inducers).
  • Use of amiodarone within 6 months prior to enrollment.
  • Concurrent use of antiarrhythmic medications.
  • Participated in clinical drug studies within 4 weeks (2 weeks for small molecule tyrosine kinase inhibitors; 6 weeks for mitomycin C and nitrosoureas) before study drug treatment. Current participation in other investigational protocols or procedures.
  • Uncontrolled infection requiring IV antibiotics, antivirals, or antifungals.
  • Known human immunodeficiency virus (HIV) infection, or active hepatitis B or C infection.
  • History of hypersensitivity to any of the study drugs or to any excipients.
  • Serious intercurrent medical or psychiatric illnesses or any other conditions that in the opinion of the Investigator would impair the ability to give informed consent or unacceptably reduce protocol compliance or safety of the study treatment.
  • Pregnant, breastfeeding, or unwilling/unable to use acceptable contraception.
  • QTc interval > 450 msec by Friderica's formula on two successive screening measurements (second measurement is required if first measurement is > 450 msec.
  • Personal or family history of long-QT syndrome.
  • Subjects who are receiving drugs that may affect QTc (eg, quinidine or moxifloxacin).

Trial locations and contacts

8 sites in 2 countries.

8 sites in 2 countries

Argentina6 sites

  • Unidad de Investigación FP Clinical Pharma en Centro Medico Integral Fitz Roy

    Acevedo, Buenos Aires F.D.

  • Hospital Britanico

    Buenos Aires, 01280

  • Sanatorio de la Providencia

    Buenos Aires, C1050AAK

  • Instituto Damic - Fundacion Rusculleda

    Córdoba, X5003DCE

  • Centro Medico San Roque

    San Miguel, Tucumán Province, T4000LAK

  • ISIS Centro Especializado

    Santa Fe, S3000CVK

Other trials in Argentina

Chile2 sites

  • Instituto de Tereplas Oncologicas Providencia INTOP

    Providencia, Santiago Metropolitan

  • Hospital Clinico San Borja Arriaran

    Santiago

Other trials in Chile

About this study

Official title: Randomized, Placebo Controlled, Double Blind Phase 1b/2 Study of U3-1287 (AMG 888) in Combination With Trastuzumab Plus Paclitaxel in Newly Diagnosed HER2 Positive Metastatic Breast Cancer (MBC)

This is a Phase 1b/2 study. In Phase 1b portion, subjects will know the treatment they are receiving . Subjects will receive U3-1287 with trastuzumab plus paclitaxel . The phase 1b portion will determine if adding U3-1287 to trastuzumab plus paclitaxel will be safe in subjects with metastatic breast cancer. In phase 2 portion, subjects will be blinded to the treatments they are receiving . Subjects will receive either trastuzumab plus paclitaxel with U3-1287 or trastuzumab plus paclitaxel and placebo.The phase 2 portion will determine if adding U3-1287 to trastuzumab plus paclitaxel will be safe and improve survival in subjects with metastatic breast cancer.

Being tested
U3-1287, Trastuzumab, Paclitaxel, Placebo
Keywords
U3-1287, Trastuzumab, Paclitaxel, newly diagnosed HER-2 positive, breast cancer, metastatic
Medical subject headings
Breast Neoplasms, Neoplasm Metastasis

What participants receive

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

  • U3-1287Drug

    U3-1287: 18 mg/kg administered intravenously once every three weeks

  • TrastuzumabDrug

    Trastuzumab: 6 mg/kg up to 8 mg/kg administered intravenously once every three weeks

  • PaclitaxelDrug

    Paclitaxel: 175 mg/m^2 administered intravenously once every three weeks

  • U3-1287Drug

    The maximum tolerated dose as determined in Phase 1b portion (between 9 mg/kg and 18 mg/kg) administered intravenously once every three weeks

  • TrastuzumabDrug

    Trastuzumab: 6 mg/kg up to 8 mg/kg administered intravenously once every three weeks

  • PaclitaxelDrug

    Paclitaxel: 175 mg/m^2 administered intravenously once every three weeks

  • PlaceboDrug

    Placebo: Dose corresponding to U3-1287 administered intravenously once every three weeks

Study groups in NCT01512199
Study groupRoleWhat they receive
U3-1287 with trastuzumab + paclitaxel (Phase 1b)ExperimentalThe Phase 1b portion is an open label, dose de escalation, single arm study designed to assess the safety and tolerability of up to 3 dose levels of U3- 1287 in combination with trastuzumab plus paclitaxel and will determine the recommended Phase 2 dose (RP2D) of U3 1287. The first cohort will receive U3- 1287 18 mg/kg intravenously (IV) in combination with trastuzumab plus paclitaxel once every 3 weeks (q3w).
Receives: Drug: U3-1287; Drug: Trastuzumab; Drug: Paclitaxel
U3-1287 with trastuzumab+paclitaxel (Ph 2)ExperimentalThe Phase 2 portion is a randomized, 2 arm, placebo controlled, double blind study designed to evaluate the safety and the efficacy of U3-1287 at the recommended phase 2 in combination with trastuzumab plus paclitaxel (experimental arm) relative to the control arm (trastuzumab plus paclitaxel and placebo).
Receives: Drug: U3-1287; Drug: Trastuzumab; Drug: Paclitaxel
Placebo with trastuzumab+paclitaxel (Ph 2)Placebo comparatorThe Phase 2 portion is a randomized, 2 arm, placebo controlled, double blind study designed to evaluate the safety and the efficacy of U3-1287 at the recommended phase 2 dose in combination with trastuzumab plus paclitaxel (experimental arm) relative to the control arm (trastuzumab plus paclitaxel and placebo).
Receives: Drug: Trastuzumab; Drug: Paclitaxel; Drug: Placebo

What is being measured

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

  1. Determination of the maximum tolerated dose based on the incidence of dose limiting toxicities (phase 1b only)

    The following criteria will also be considered a dose limiting toxicity (DLT).

    • > 15% decrease in left ventricular ejection fraction (LVEF) from baseline or an LVEF value > 10% below lower limit of normal (LLN)
    • Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 3 x the upper limit of normal (ULN) AND total bilirubin > 2 x ULN or international normalized ratio (INR) > 1.5

    Measured: Study start to approximately 16 weeks

  2. Progression Free Survival (Phase 2 only)

    Tumor assessment will be conducted every 6 weeks independent of treatment cycle in accordance with Response Evaluation Criteria in Solid Tumors (RECIST version 1.1)

    Measured: 52 weeks (Start to end of Phase 2)

Secondary outcomes (18)

  1. Pharmacokinetics (Area Under Curve) of U3-1287 when combined with trastuzumab plus paclitaxel

    Measured: Pharmacokinetic blood samples will be taken on days 1, 2, 3, 8, 15, end of study (phase 1b) and during cycles 1-5, 9, 13, and at the end of study (Phase 2)

  2. Pharmacokinetics (Area Under Curve Extrapolation Percent) of U3-1287 when combined with trastuzumab plus paclitaxel

    Measured: Pharmacokinetic blood samples will be taken on days 1, 2, 3, 8, 15, end of study (phase 1b) and during cycles 1-5, 9, 13, and at the end of study (Phase 2)

  3. Pharmacokinetics (C-max, C-min) of U3-1287 when combined with trastuzumab plus paclitaxel

    Measured: Pharmacokinetic blood samples will be taken on days 1, 2, 3, 8, 15, end of study (phase 1b) and during cycles 1-5, 9, 13, and at the end of study (Phase 2)

  4. Pharmacokinetics (T-max) of U3-1287 when combined with trastuzumab plus paclitaxel

    Measured: Pharmacokinetic blood samples will be taken on days 1, 2, 3, 8, 15, end of study (phase 1b) and during cycles 1-5, 9, 13, and at the end of study (Phase 2)

  5. Pharmacokinetics (Terminal Elimination Rate Constant) of U3-1287 when combined with trastuzumab plus paclitaxel

    Measured: Pharmacokinetic blood samples will be taken on days 1, 2, 3, 8, 15, end of study (phase 1b) and during cycles 1-5, 9, 13, and at the end of study (Phase 2)

  6. Pharmacokinetics (Terminal Half-Life) of U3-1287 when combined with trastuzumab plus paclitaxel

    Measured: Pharmacokinetic blood samples will be taken on days 1, 2, 3, 8, 15, end of study (phase 1b) and during cycles 1-5, 9, 13, and at the end of study (Phase 2)

  7. Pharmacokinetics (Volume of Distribution) of U3-1287 when combined with trastuzumab plus paclitaxel

    Measured: Pharmacokinetic blood samples will be taken on days 1, 2, 3, 8, 15, end of study (phase 1b) and during cycles 1-5, 9, 13, and at the end of study (Phase 2)

  8. Pharmacokinetics (Total Body Clearance) of U3-1287 when combined with trastuzumab plus paclitaxel

    Measured: Pharmacokinetic blood samples will be taken on days 1, 2, 3, 8, 15, end of study (phase 1b) and during cycles 1-5, 9, 13, and at the end of study (Phase 2)

  9. The best overall tumor response rate (Phase 1b)

    The best overall tumor response is defined as the best response among all overall responses (in the order of Complete Response, Partial Response, Stable Disease, and Progressive Disease as per RECIST Version 1.1) recorded from the start of treatment.

    Measured: Study start to 16 weeks

  10. Human anti-human antibody (HAHA) profile for U3-1287 (Phase 1b only)

    The presence of HAHA (anti-U3-1287 neutralizing antibody) in serum will be assessed. To determine the presence of HAHA, blood samples will be taken preinfusion on Day 1 and at end of study treatment visit.

    Measured: Study start to 16 weeks

  11. Human anti-human antibody (HAHA) profile for U3-1287 (Phase 2)

    The presence of HAHA (anti-U3-1287 neutralizing antibody) in serum will be assessed. To determine the presence of HAHA, blood samples will be taken preinfusion on Day 1 of Cycles 1, 2, 3, 5, 9, and 13, and at end of study treatment visit.

    Measured: Study start to 52 weeks

  12. Overall survival (Phase 2)

    Measured: Study start to 52 weeks

  13. Duration of response (Phase 2)

    Measured: Study start to 52 weeks

  14. Time to response (Phase 2)

    Measured: Study start to 52 weeks

  15. Time to progression (Phase 2)

    Measured: Study start to 52 weeks

  16. Duration of stable disease (Phase 2)

    Measured: Study start to 52 weeks

  17. The best overall tumor response rate (Phase 2)

    The best overall tumor response is defined as the best response among all overall responses (in the order of Complete Response, Partial Response, Stable Disease, and Progressive Disease as per RECIST Version 1.1) recorded from the start of treatment.

    Measured: Study start to 52 weeks

  18. Disease control rate (Phase 2)

    The disease control rate is defined as the proportion of subjects with the best overall response of stable disease or better

    Measured: Study start to 52 weeks

Timeline

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

  1. First posted19 Jan 2012 (estimated)
  2. Study startNov 2011
  3. Primary completion28 Jan 2015
  4. Study completion28 Jan 2015

Why it stopped: Improved, different standard of care caused business decision to terminate

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
Randomised
Intervention model
Parallel groups
Masking
Double blind
Who is masked
Participant, Investigator
Enrolment
29 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT01512199
Sponsor's protocol ID
U31287-A-U202
Status last verified
Oct 2017
First submitted
9 Jan 2012
Last updated
18 Oct 2017
Results posted
No
Data monitoring committee
Yes

Questions about this trial

What is this clinical trial studying?

A Phase 1/2 study testing U3-1287, Trastuzumab and Paclitaxel in people with Metastatic Breast Cancer, run by Daiichi Sankyo at 8 sites in 2 countries.

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 21 inclusion and 24 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 Oct 2017. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 8 sites in Argentina, Chile. 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. Some participants in this study may receive a placebo. 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?

The study was stopped early (reason given: Improved, different standard of care caused business decision to terminate). Results are not available in the source record.

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?

Determination of the maximum tolerated dose based on the incidence of dose limiting toxicities (phase 1b only) (time frame: Study start to approximately 16 weeks). 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 NCT01512199.

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 Oct 2017.

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