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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/show/NCT02129556




Registration number
NCT02129556
Ethics application status
Date submitted
24/04/2014
Date registered
2/05/2014
Date last updated
15/02/2019

Titles & IDs
Public title
Anti-PD-1 Monoclonal Antibody in Advanced, Trastuzumab-resistant, HER2-positive Breast Cancer
Scientific title
A Phase Ib/II Trial Evaluating the Efficacy of MK-3475 and Trastuzumab in Patients With Trastuzumab-resistant, HER2-positive Metastatic Breast Cancers
Secondary ID [1] 0 0
2013-004770-10
Secondary ID [2] 0 0
IBCSG 45-13 / BIG 4-13
Universal Trial Number (UTN)
Trial acronym
PANACEA
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Metastatic Breast Cancer 0 0
Condition category
Condition code
Cancer 0 0 0 0
Breast

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - MK-3475

Experimental: MK-3475 with trastuzumab (single arm) - Phase Ib: MK-3475 at dose of 2 mg/kg or 10 mg/kg (i.v.), or a fall-back dose of 1 mg/kg, together with trastuzumab 6mg/kg by (i.v.) once every 3 weeks.
Phase II: MK-3475 at a flat dose of 200mg (i.v.) together with trastuzumab 6mg/kg (i.v.) once every 3 weeks until progression, lack of tolerability, or 24 months of treatment.
A dose of 8mg/kg trastuzumab will be used in cycle 1 if prior treatment with trastuzumab was stopped more than 3 months before.


Treatment: Drugs: MK-3475
The phase Ib trial will determine the recommended dose from three MK-3475 dose levels: 1mg/kg, 2 mg/kg or 10 mg/kg.

Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Dose-Limiting Toxicity (DLT) of MK-3475 in Combination With Trastuzumab - Determination of dose-limiting toxicity (DLT) which is defined as an adverse event or abnormal laboratory value assessed as suspected to be trial treatment related (possible, probable or definite) and unrelated to disease or disease progression. Toxicities and lab values will be graded according to the NCI CTCAE (v4.0).
Any grade-3 or greater non-hematological adverse event lasting at least one week;
Any grade-4 hematological toxicity; or,
Any adverse event resulting in a delay starting cycle 2 of more than 14 days.
Timepoint [1] 0 0
Within the first 21 days
Primary outcome [2] 0 0
Objective Response Rate (ORR) - Confirmed CR or PR as best overall response. At the time of each restaging, patients will be classified as achieving complete response (CR), partial response (PR), stable disease (SD), progressive disease (PD), or non-evaluable for response according to RECIST (Version 1.1) criteria.
Timepoint [2] 0 0
Clinical and radiological tumor assessment will be performed by CT scan or MRI at baseline, at weeks 12, 18 and 24, then every 12 weeks until progression, or 24 weeks after stop of treatment if before progression.
Secondary outcome [1] 0 0
Duration of Response (DoR) - Duration of response (DoR) is defined among patients with objective response (confirmed CR or PR as best overall response) as the interval between dates of first documentation of objective response and first documentation of progressive disease. In the absence of documented progressive disease, follow-up will be censored at date of last disease assessment.
Timepoint [1] 0 0
From date of first documentation of objective response until first documentation of progressive disease, up to 24 weeks after stop of treatment (=30 months)
Secondary outcome [2] 0 0
Time to Progression (TTP) - Time to progression (TTP) defined as the interval between the dates of the start of trial treatment and first documentation of progressive disease. In the absence of documented progressive disease, follow-up will be censored at date of last disease assessment
Timepoint [2] 0 0
From the first trial treatment until first documentation of progressive disease up to 24 weeks after stop of treatment (=30 months)
Secondary outcome [3] 0 0
Disease Control Rate (DCR) - The proportion of patients with best confirmed RECIST response of CR, PR, or duration of SD of at least 24 weeks (measured from first dose of trial treatment).
Timepoint [3] 0 0
From the start of trial treatment until confirmed CR, PR, or SD lasting for 24 weeks or longer
Secondary outcome [4] 0 0
Progression-Free Survival (PFS) - The interval between the dates of the first dose of trial treatment until first documentation of disease progression or death, whichever occurs first. Patients with new non-breast cancer malignancy must continue to be followed for progression of the original breast cancer. For patients without progression, follow-up is censored at the date of last disease assessment without progression, unless death occurs within 12 weeks following the date last known progression-free, in which case the death will be counted as a PFS event.
Timepoint [4] 0 0
From the date of first treatment dose until documented disease progression or death from any cause. whichever occur first, assessed up to 30 months
Secondary outcome [5] 0 0
Overall Survival (OS) at 12 Months - OS is defined as the time from the first dose of trial treatment to death from any cause. For patients who are lost to follow-up or who have no documentation of death at the time of final analysis, follow-up is censored at the date of last assessment of vital status. OS at 12 months by Kaplan-Meier estimates.
Timepoint [5] 0 0
Time from start of trial treatment to death from any cause, assessed up to 30 months

Eligibility
Key inclusion criteria
Inclusion criteria for screening:

- Female gender

- Age = 18 years

- Histologically confirmed breast adenocarcinoma that is unresectable loco-regional, or
metastatic.

- Locally confirmed HER2-positivity (immunohistochemistry score 3+) or
ERBB2-amplification (Ratio ERBB2/centromeres =2.0 or mean gene copy number = 6) of
primary tumor or of biopsy from metastatic or unresectable loco-regional lesion.

- Trastuzumab resistant disease, defined by:

- progression of disease while on-treatment with trastuzumab

- recurrence while on adjuvant trastuzumab or within 12 months of completing
adjuvant trastuzumab

- Any number of prior lines of anti-HER2 therapy acceptable. Patients for whom the
treatment with the current first-line combination of trastuzumab, pertuzumab and
taxanes is not an option can be considered for enrollment

- If a patient has received a subsequent anti-HER2 therapy, she must also have
progressed on the subsequent therapy.

- Presence of at least one measurable lesion (RECIST 1.1)

- LVEF =50%

- Patient agrees to submit an FFPE tumor biopsy for central confirmation of HER2
positivity and central assessment of PD-L1 status.

- Written Informed Consent (IC) for screening procedures and trial participation must be
signed and dated by the patient and the Investigator prior to screening.

- Written consent to biological material submission, indicating the patient has been
informed of and agrees to tissue and blood material use, transfer and handling, must
be signed and dated by the patient and the investigator prior to any procedures
specific for this trial, including consent to translational research on FFPE and fresh
frozen tumor biopsies in case the patient is enrolled into the trial.

- The patient has been informed of and agrees to data transfer and handling, in
accordance with national data protection guidelines.

- Eastern Cooperative Oncology Group (ECOG) Performance Status 0-1

- Life expectancy >3 months.

- Hematopoietic status:

- Absolute neutrophil count = 1.5 × 109/L,

- Platelet count = 100 × 109/L,

- Hemoglobin = 9 g/dL

- Hepatic status:

- Serum total bilirubin = 1.5 × upper limit of normal (ULN). In the case of known
Gilbert's syndrome, a higher serum total bilirubin (< 2 × ULN) is allowed.

- AST and ALT = 2.5 × ULN; if the patient has liver metastases, ALT and AST must be
= 5 × ULN.

- Renal status:

- Creatinine = 1.5 ×ULN or creatinine clearance > 60 ml/min

- Proteinuria <1 g/day

- International Normalized Ratio (INR) or Prothrombin Time (PT) =1.5 × ULN unless
patient is receiving anticoagulant therapy as long as PT or PTT (partial
thromboplastin time) is within therapeutic range of intended use of anticoagulant.

Inclusion criteria for enrollment:

All inclusion criteria for screening, plus:

- Central lab confirmation on a metastatic biopsy (or biopsy from unresectable
loco-regional disease) of:

- HER2-positivity (immunohistochemistry score 3+) or ERBB2- amplification (Ratio
ERBB2/centromeres =2.0 or mean gene copy number = 6),

- Presence of PD-L1 expression assessed by IHC (during the phase II portion of the
trial a parallel, secondary cohort of 15 patients with PD-L1 negative disease
will be enrolled)

- Patient agrees to submit tumor tissue for translational research:

- tissue biopsy from unresectable loco-regional or metastatic disease obtained =1
year prior to enrollment or new tissue material from a recently obtained surgical
or diagnostic biopsy. For patients who have presented with stage 4 disease de
novo, a biopsy taken from the presumed primary breast lesion is acceptable
(provided this was taken =1 year prior to enrollment).

- if available: FFPE tumor block from primary surgery or diagnostic biopsy.

- if available: pre-treatment fresh frozen tumor biopsy.

- if feasible: FFPE tumor block from post-treatment biopsy will be taken at time of
disease progression or end of all treatment if ended prior to progression. This
re-biopsy is strongly advised.

- if feasible: fresh frozen tumor biopsy from post-treatment biopsy will be taken
at time of disease progression or end of all treatment if ended prior to
progression.

- Patient agrees to submit baseline (pre-treatment) blood and serial plasma for
translational research

- For patient of childbearing potential, negative serum pregnancy test. Pregnancy test
has to be repeated within 72h before treatment start.

- All anti-cancer treatment including endocrine therapy, with the exception of
trastuzumab, must stop 3 weeks prior to first dose of trial treatment.
Minimum age
18 Years
Maximum age
No limit
Gender
Females
Can healthy volunteers participate?
No
Key exclusion criteria
Exclusion criteria for screening:

- Prior therapy with other anti-PD-1, anti- PD-L1, L2 or anti-CTLA4 therapy.

- No FFPE material to centrally assess HER2-positivity and PD-L1 expression.

- Known Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies), or positive for
Hepatitis B (HBsAg reactive) or Hepatitis C (HCV RNA [qualitative]).

- Interstitial lung disease

- History of or active pneumonitis requiring treatment with steroids

- Active central nervous system metastases, as indicated by clinical symptoms, cerebral
edema, and/or progressive growth (patients with history of CNS metastases or spinal
cord compression are eligible if they are clinically and radiologically stable for at
least 4 weeks before first dose of investigational product and have not required
high-dose steroid treatment in the last 4 weeks).

- Leptomeningeal disease

- History of clinically significant or uncontrolled cardiac disease, including
congestive heart failure (New York Heart Association functional classification =3),
angina, myocardial infarction or ventricular arrhythmia.

- Previous severe hypersensitivity reaction to treatment with another monoclonal
antibody.

- Active infection requiring systemic therapy.

- Chronic systemic therapy with immunosuppressive agents including cortico¬steroids.

- Concurrent disease or condition that would make the patient inappropriate for trial
participation or any serious medical disorder that would interfere with the patient's
safety.

- Known history of uncontrolled hypertension (= 180/110), unstable diabetes mellitus,
dyspnea at rest, or chronic therapy with oxygen.

- Dementia, altered mental status, or any psychiatric condition that would prevent the
understanding or rendering of Informed Consent.

- Treatment with an investigational agent in the 4 weeks before enrollment.

- Active autoimmune disease or a documented history of autoimmune disease, or a syndrome
that requires systemic steroids or immunosuppressive agents. Patients with vitiligo or
resolved childhood asthma/atopy would be an exception to this rule. Patients that
require intermittent use of bronchodilators or local steroid injections would not be
excluded from the trial. Patients with hypothyroidism stable on hormone replacement or
Sjögren's syndrome will not be excluded from the trial.

- Chemotherapy, radioactive therapy, and/or biological cancer therapy within 3 weeks
prior to the first trial dose and has not recovered to CTCAE v.4 grade 1 or better
from adverse events.

- Pregnant or lactating women; lactation has to stop before enrollment.

- The patient of childbearing potential who is unwilling to use highly effective
contraception during treatment and up to 7 months after stop of trial treatment.
Acceptable methods are intrauterine devices (without hormones), bilateral tubal
occlusion, vasectomized partner or total abstinence. Oral, injectable, or implant
hormonal contraceptives are not allowed.

- Unresolved or unstable, serious adverse events from prior administration of another
investigational drug.

- Active or uncontrolled infection CTCAE v.4 grade 2 or higher.

- Live vaccines within 30 days prior to the first dose of trial therapy and during trial
treatment.

Exclusion criteria for enrollment:

- All exclusion criteria for screening apply for enrollment as well. Excluded are
especially patients who have received any of the treatments below:

- Live vaccines within 30 days prior to the first dose of trial therapy and during trial
treatment.

- History of CNS metastases or spinal cord compression if they have not been clinically
stable for at least 4 weeks before first dose of investigational product and require
high-dose steroid treatment.

- Treatment with an investigational agent in the 4 weeks before enrollment.

- Patient has not recovered to CTCAE v.4 grade 1 or better from adverse events of prior
therapy, except alopecia grade 2.

- Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies), or positive for Hepatitis B
or Hepatitis C.

Study design
Purpose of the study
Treatment
Allocation to intervention
N/A
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
Phase
Phase 1/Phase 2
Type of endpoint(s)
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
Recruitment hospital [1] 0 0
Peter MacCallum Cancer Centre - East Melbourne
Recruitment hospital [2] 0 0
Westmead Hospital - Westmead
Recruitment postcode(s) [1] 0 0
- East Melbourne
Recruitment postcode(s) [2] 0 0
- Westmead
Recruitment outside Australia
Country [1] 0 0
Austria
State/province [1] 0 0
Vienna
Country [2] 0 0
Belgium
State/province [2] 0 0
Brussels
Country [3] 0 0
Belgium
State/province [3] 0 0
Liège
Country [4] 0 0
France
State/province [4] 0 0
Angers
Country [5] 0 0
France
State/province [5] 0 0
Bordeaux
Country [6] 0 0
France
State/province [6] 0 0
Lyon
Country [7] 0 0
France
State/province [7] 0 0
Villejuif
Country [8] 0 0
Italy
State/province [8] 0 0
Milan
Country [9] 0 0
Italy
State/province [9] 0 0
Prato

Funding & Sponsors
Primary sponsor type
Other
Name
International Breast Cancer Study Group
Address
Country
Other collaborator category [1] 0 0
Other
Name [1] 0 0
Breast International Group
Address [1] 0 0
Country [1] 0 0

Ethics approval
Ethics application status

Summary
Brief summary
Panacea is a phase Ib/II trial evaluating the efficacy of MK-3475 and trastuzumab in patients
with trastuzumab-resistant, HER2- positive metastatic breast cancers
Trial website
https://clinicaltrials.gov/show/NCT02129556
Trial related presentations / publications
Slamon DJ, Leyland-Jones B, Shak S, Fuchs H, Paton V, Bajamonde A, Fleming T, Eiermann W, Wolter J, Pegram M, Baselga J, Norton L. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med. 2001 Mar 15;344(11):783-92.
Hurvitz SA, Betting DJ, Stern HM, Quinaux E, Stinson J, Seshagiri S, Zhao Y, Buyse M, Mackey J, Driga A, Damaraju S, Sliwkowski MX, Robert NJ, Valero V, Crown J, Falkson C, Brufsky A, Pienkowski T, Eiermann W, Martin M, Bee V, Marathe O, Slamon DJ, Timmerman JM. Analysis of Fc? receptor IIIa and IIa polymorphisms: lack of correlation with outcome in trastuzumab-treated breast cancer patients. Clin Cancer Res. 2012 Jun 15;18(12):3478-86. doi: 10.1158/1078-0432.CCR-11-2294. Epub 2012 Apr 13.
Denkert C, Loibl S, Noske A, Roller M, Müller BM, Komor M, Budczies J, Darb-Esfahani S, Kronenwett R, Hanusch C, von Törne C, Weichert W, Engels K, Solbach C, Schrader I, Dietel M, von Minckwitz G. Tumor-associated lymphocytes as an independent predictor of response to neoadjuvant chemotherapy in breast cancer. J Clin Oncol. 2010 Jan 1;28(1):105-13. doi: 10.1200/JCO.2009.23.7370. Epub 2009 Nov 16. Erratum in: J Clin Oncol. 2010 Feb 1;28(4):708.
Loi S, Sirtaine N, Piette F, Salgado R, Viale G, Van Eenoo F, Rouas G, Francis P, Crown JP, Hitre E, de Azambuja E, Quinaux E, Di Leo A, Michiels S, Piccart MJ, Sotiriou C. Prognostic and predictive value of tumor-infiltrating lymphocytes in a phase III randomized adjuvant breast cancer trial in node-positive breast cancer comparing the addition of docetaxel to doxorubicin with doxorubicin-based chemotherapy: BIG 02-98. J Clin Oncol. 2013 Mar 1;31(7):860-7. doi: 10.1200/JCO.2011.41.0902. Epub 2013 Jan 22.
Public notes

Contacts
Principal investigator
Name 0 0
Sherene Loi, MD
Address 0 0
Department of Medical Oncology,Peter MacCallum Cancer Centre,East Melbourne, Victoria, Australia
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries

Summary results
Other publications