| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
Previously Treated, Locally Advanced and Unresectable
or Metastatic Triple Negative Breast Cancer (TNBC) or
Triple Negative Inflammatory Breast Cancer (TN-IBC) |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
To assess anti-tumor activity of the combination
of BGB324 and pembrolizumab |
|
| E.2.2 | Secondary objectives of the trial |
To assess the safety of BGB324 and pembrolizumab when given in combination
To further assess the anti-tumor activity of the combination of BGB324 and pembrolizumab
The number and frequency of adverse events; assessment of safety laboratory parameters,
vital signs and ECGs
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Provision of signed informed consent.
2. Age 18 years or older at the time of provision of informed consent.
3. Histopathologically or cytologically documented TNBC or TN-IBC. Tumors must
have been confirmed negative for ER and PR by IHC (<1% positive tumor nuclei, as
per ASCO-CAP guideline recommendations3) and negative for HER2 by IHC or
fluorescent or chromogenic in situ hybridization (FISH or CISH). Patients with
equivocal HER2 results by IHC should have their negativity status confirmed by FISH.
4. Locally advanced and unresectable or metastatic TNBC or triple negative
inflammatory breast cancer.
5. Received one or more prior therapies for TNBC or TN-IBC, which may include
adjuvant, neo-adjuvant and metastatic therapy, and must have included a prior taxane
and/or anthracycline-based therapy
6. Has measurable disease as defined by RECIST 1.12 on computed tomography (CT) or
magnetic resonance imaging (MRI) and as determined by the site study team. Tumor
lesions situated in a previously irradiated area are considered measurable if progression
has been demonstrated in such lesions.
7. Provision of suitable tumor tissue for the analysis of Axl kinase expression and PD-L1
expression. Suitable tumor tissue must consist of a minimum of newly acquired (fresh)
tumor tissue sample (as a FFPE block), together with either further newly acquired
tumor tissue (i.e. further FFPE block) or an archival tumor tissue sample (as a further
FFPE block or further 10 unstained slides). See Section 5.3.13 for further details.
8. Eastern Cooperative Oncology Group (ECOG) performance score 0 or 1 [Appendix
A].
9. Life expectancy of at least 3 months.
10. Adequate organ function confirmed at Screening and within 10 days of initiating
treatment, as evidenced by:
a. Platelet count ≥100,000 /mm3;
b. Hemoglobin ≥9.0 g/dL (≥5.6 mmol/L);
c. Absolute neutrophil count (ANC) >1,500 /mm3;
d. Alanine aminotransferase (ALT) and Aspartate aminotransferase (AST) ≤2.5
times the upper limit of normal (ULN), or ≤5 times the ULN for patients with
liver metastases;
e. Total bilirubin ≤1.5 times the ULN, or direct bilirubin <ULN for patients with
total bilirubin levels >1.5xULN;
f. Creatinine ≤1.5 times the ULN and calculated creatinine clearance >60 mL/min
(by Cockcroft Gault formula; see Appendix B);
g. International Normalized Ratio (INR) or Prothrombin Time (PT) ≤1.5 times the
ULN and Activated Partial Thromboplastin Time (aPTT) ≤1.5 times the ULN.
Note: If patient is receiving anticoagulant therapy, then PT or PTT must be
within therapeutic range of intended use of anticoagulants;
h. LDH ≤2.5 times the ULN.
11. Female patients of childbearing potential must have a negative pregnancy test (either
urine or serum pregnancy test) within 72 hours prior to the first dose of study treatment.
If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test
will be required.
12. Have resolution of toxic effect(s) of the most recent prior chemotherapy to Grade 1 or
less (except alopecia). If the patient received major surgery or radiation therapy of >30
Gy, they must have recovered from the toxicity and/or complications from the
intervention.
13. Patients of reproductive potential must be willing to practice highly effective methods
of contraception (such as those described in Section 6.13) throughout the study and for
120 days after the last dose of study medication. Abstinence is acceptable if this is the
usual lifestyle of the patient. Female patients are considered NOT of childbearing
potential if they have a history of surgical sterility or evidence of post-menopausal
status defined as any of the following:
a. ≥45 years of age and has not had menses for more than 1 year;
b. Amenorrheic for >2 years without a hysterectomy and oophorectomy and a
follicle stimulating hormone (FSH) value in the postmenopausal range upon
Screening evaluation and oestradiol <30 pg/mL;
c. Post hysterectomy, oophorectomy or tubal ligation. |
|
| E.4 | Principal exclusion criteria |
1. Has disease that is suitable for local therapy administered with curative intent.
2. More than 3 previous lines of therapy in the metastatic setting.
3. Has received prior therapy with an immunomodulatory agent.
4. Has a known additional malignancy that is progressing or requires active treatment.
5. Has known active central nervous system (CNS) metastases and/or carcinomatous
meningitis.
6. History of the following cardiac conditions:
a. Congestive cardiac failure of >Grade II severity according to the
NYHA
b. Ischemic cardiac event including myocardial infarction within 3 months prior to
first dose;
c. Uncontrolled cardiac disease, including unstable angina, uncontrolled
hypertension or need to change medication due to lack of disease control within 6
weeks prior to the provision of consent;
d. History or presence of sustained bradycardia (≤55 BPM), left bundle branch
block, cardiac pacemaker or ventricular arrhythmia.
e. Family history of long QTc syndrome; personal history of long QTc syndrome
or previous drug-induced QTc prolongation of at least Grade 3 (QTc >500 ms).
7. Abnormal left ventricular ejection fraction on echocardiography or MUGA
8. Current treatment with any agent known to cause Torsades de Pointes which cannot
be discontinued at least five half-lives or two weeks prior to the first dose of study
treatment.
9. Screening 12-lead ECG with a measurable QTc interval according to Fridericia’s
correction >450 ms.
10. Is currently participating and receiving study therapy or has participated in a study of
an investigational agent and received study therapy or used an investigational device
within 4 weeks of the first dose of study treatment.
11. Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy
within 2 weeks prior to study Day 1 or who has not recovered from AEs due to a previously administered agent.
12. Received an anti-cancer monoclonal antibody (mAb) within 4 weeks prior to the first
dose of study treatment or who has not recovered from AEs
due to agents administered more than 4 weeks earlier.
13. Major surgery within 28 days prior to start of study treatment and failure to have
recovered adequately from the toxicity and/or complications from the intervention
prior to the first dose of study treatment.
14. Received transfusion of blood products (including platelets or red blood cells) or
administration of colony stimulating factors (including G-CSF, GM-CSF or
recombinant erythropoetin) within 4 weeks prior to the first dose of study treatment.
15. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any
other form of immunosuppressive therapy within 7 days prior to the first dose of study
treatment.
16. Active autoimmune disease that has required systemic treatment in past 2 years
Note: Replacement therapy is not considered a
form of systemic treatment.
17. Known history of human immunodeficiency virus (HIV 1/2 antibodies)
18. Has known active infection with Hepatitis B or Hepatitis C
19. Has received a live-virus vaccination within 30 days of planned treatment start. Note:
Seasonal flu vaccines that do not contain live virus are permitted.
20. Has a history of (non-infectious) pneumonitis that required steroids or current
pneumonitis.
21. Has a history of interstitial lung disease.
22. Inability to swallow or tolerate oral medication.
23. Existing gastrointestinal disease affecting drug absorption such as celiac disease or
Crohn’s disease, or previous bowel resection which is considered to be clinically
significant or could interfere with absorption.
24. Known lactose intolerance.
25. Requires vitamin K antagonists. Note: Patients receiving low doses prescribed to
maintain the patency of venous access devices may be included. Factor Xa antagonists
are permitted.
26. Treatment with any of the following: histamine receptor 2 inhibitors, proton pump
inhibitors or antacids within 7 days of start of study treatment.
27. Treatment with any medication which is predominantly metabolized by CYP3A4 and
has a narrow therapeutic index.
28. Known hypersensitivity to BGB324, pembrolizumab, or any of their excipients.
29. Has an active infection requiring systemic therapy (apart from cutaneous infections).
30. Has a history or current evidence of any condition, therapy, or laboratory abnormality
that, in the opinion of the Investigator, might confound the results of the trial, interfere
with the patient’s participation and compliance in the trial, or means it is not in the best
interests of the patient to participate.
31. Is pregnant or breastfeeding, or expecting to conceive or father children within the
projected duration of the trial, starting from Screening through to 120 days after the
last dose of study treatment.
32. Has known psychiatric or substance abuse disorders that would interfere with
cooperation with the requirements of the trial.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
The study will utilize a 2-stage, single arm, extension of Simon’s 2-stage design1 with one
(efficacy) interim and a final analysis. The interim analysis will be conducted when 28 patients
are evaluable for Objective Response Rate (ORR).
Recruitment to the study will be halted once 28 evaluable patients have been entered and whilst
the Stage 1 interim analysis is conducted. Recruitment will recommence if the decision is made
to continue to the maximum of 56 evaluable patients. |
|
| E.5.2 | Secondary end point(s) |
Duration of Response
Disease Control Rate
Time to progression
Survival at 12 months
Response by Biomarker expression
Safety
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
The study will utilize a 2-stage, single arm, extension of Simon’s 2-stage design1 with one
(efficacy) interim and a final analysis. The interim analysis will be conducted when 28 patients
are evaluable for Objective Response Rate (ORR).
Recruitment to the study will be halted once 28 evaluable patients have been entered and whilst
the Stage 1 interim analysis is conducted. Recruitment will recommence if the decision is made
to continue to the maximum of 56 evaluable patients. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 1 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 3 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Norway |
| Spain |
| United Kingdom |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
The study will be completed when either:
• The study is terminated at the interim analysis following the DRC review of the ORR
and risk/benefit for all patients included in the interim analysis. The interim analysis
will occur once 28 evaluable patients have had the potential to be followed for at least
24 weeks.
OR
• The study will complete and the final analysis will occur once all patients (planned 56
evaluable patients) have had the potential to be followed for at least 24 weeks. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 11 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 11 |
Print
