NOvel Immunotherapy strategies for advanced Triple negative breast Cancer (TNBC) patients: TONIC-3 trial

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Het Nederlands Kanker Instituut-Antoni van Leeuwenhoek Ziekenhuis Stichting

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

12 Jun 2024 → ongoing

Decision date (initial)

2024-01-15

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy, Safety, Efficacy

To determine the efficacy and safety of novel immunomodulatory strategies in TNBC patients with
advanced disease

Secondary objectives 6

1. Efficacy of novel immunotherapy combinations
2. To explore the utility of the patient-derived tumor-fragment (PDTF) platform as ex vivo platform for response prediction
3. To explore the feasibility of generating TNBC molecular subtype data before start of treatment
4. To test novel treatment strategies in well-defined subgroups of TNBC patients (based on clinical features or well-defined biomarker)
5. To gain more insight in the composition and cell state of the tumor microenvironment (TME) of advanced TNBC and assess treatment-induced changes
6. To explore biomarkers to predict response to a particular treatment approach

Conditions and MedDRA coding

advanced TNBC, eg. irresectable recurrent disease or metastatic disease

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 12

1. Metastatic or incurable locally advanced triple negative breast cancer with confirmation of ER and HER2 negativity (ER <10% and HER2 IHC 0, 1+ or 2+ in the absence of amplification as determined by in situ hybridization, independent of progesterone receptor expression) on a histological biopsy of a metastatic lesion
2. Patients with PD-L1 negative disease determined using the Combined Positivity Score (CPS<10) (Dako 22C3 immunohistochemistry) OR previously treated with anti-PD(L)1 in the (neo)adjuvant or metastatic setting (irrespective of PD-L1 status)
3. Metastatic lesion accessible for histological biopsy (Mandatory biopsies: baseline, after 1 cycle of treatment. Optional biopsies: 12-weeks, at progression).
4. 18 years or older
5. WHO performance status of 0 or 1
6. Maximum of three lines of chemotherapy (including antibody-drug conjugates and PARP-inhibitors) for metastatic disease and with evidence of progression of disease.
7. Measurable or evaluable disease according to RECIST 1.1
8. Disease Free Interval (defined as time between first diagnosis or locoregional recurrence and first metastasis) longer than 1 year. This does not apply to patients with de novo metastatic disease or patients who did not receive (neo)adjuvant chemotherapy.
9. WBC ≥ 2.0x109/L, ANC ≥ 1.5 x 109/L(without G-CSF use in last 4 weeks), platelets ≥100 x 109/L, Hemoglobin ≥ 5.0 mmol/L
10. Bilirubin < 1.5 x upper limit of the normal range (ULN)(except for participants with Gilbert Syndrome <3x ULN); alkaline phosphatase < 2.5 x ULN (< 5 x ULN in case of liver metastases, and < 7 x ULN N22TON, version 1.0 dd 21 July 2023 10 in case of bone metastases); transaminases (ASAT/ALAT) < 3 x ULN (and < 5 x ULN in case of liver metastases), LDH < 2xULN
11. Calculated (Cockcroft-Gault) or measured creatinine clearance > 40 mL/min
12. Signed informed consent

Exclusion criteria 17

1. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris
2. Symptomatic brain metastases, subjects with asymptomatic brain metastases are eligible. Subjects who received prior treatment for brain metastases should be free of progression on magnetic resonance imaging (MRI) for at least 4 weeks after treatment is completed and prior to first dose of study drug administration. There must also be no requirement for immunosuppressive doses of systemic corticosteroids (> 10 mg/day prednisone equivalents) for at least 2 weeks prior to study drug administration
3. History of leptomeningeal disease localization
4. History of having received other anticancer therapies within 2 weeks of start of the study drug
5. History of severe allergic anaphylactic reactions to chimeric or humanized antibodies or fusion proteins
6. Known hypersensititivy to Chinese hamster ovary cell products or to any component of the atezolizumab or tiragolumab formulation
7. History of immunodeficiency, autoimmune disease, conditions requiring immunosuppression (>10 mg daily prednisone equivalents) or chronic infections. Subjects with vitiligo, diabetes mellitus type I, psoriasis not requiring systemic treatment or resolved childhood asthma/atopy would be an exception to this rule. Subjects that require intermittent use of bronchodilators, inhaled steroids, or local steroid injections would not be excluded from the study. Subjects with hypothyroidism stable on hormone replacement, Sjøgren’s syndrome or conditions not expected to recur in the absence of an external trigger will not be excluded from the study. Adrenal replacement doses >10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease
8. Prior treatment with an anti-CTLA4 or anti-TIGIT antibody
9. Administration of live vaccine within 30 days of planned start of study therapy.
10. Active other cancer
11. Positive test for hepatitis B surface virus surface antigen (HBsAg) or hepatitis C virus ribonucleic acid (HCV antibody) indicating acute or chronic infection. Specified by: positive hepatitis B surface antibody (HBsAb) test at screening, or negative HBsAb at screening accompanied by either of the following: negative total hepatitis B core antibody (HBcAb), positive total HBcAb test followed by quantitative hepatitis B virus (HBV) DNA < 500 IU/mL. The HBV DNA test will be performed only for patients who have a negative HBsAg test, a negative HBsAb test, and a positive total HBcAb test. Specific for hepatitis C screening: positive HCV antibody test followed by a negative HCV RNA test at screening. The HCV RNA test will be performed only for patients who have a positive HCV antibody test
12. Sign of active TB
13. Positive HIV test at screening
14. Positive EBV viral capsid antigen immunoglobulin M (IgM) test at screening
15. History of uncontrolled serious medical or psychiatric illness
16. Presence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule
17. Current pregnancy pregnancy or breastfeeding. For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraception: Women must remain abstinent or use contraceptive methods with a failure rate of < 1% per year during the treatment period and for 90 days after the final dose of tiragolumab, 5 months after the final dose of atezolizumab. A woman is considered to be of childbearing potential if she is postmenarchal, has not reached a postmenopausal state (≥ 12 continuous months of amenorrhea with no identified cause other than menopause), and has not undergone surgical sterilization (i.e., removal of ovaries, fallopian tubes, and/or uterus) or another cause as determined by the investigator (e.g., Müllerian agenesis). Per this definition, a woman with a tubal ligation is considered to be of childbearing potential. (The definition of childbearing potential may be adapted for alignment with local guidelines or regulations). Examples of contraceptive methods with a failure rate of < 1% per year include bilateral tubal ligation, male sterilization, hormonal contraceptives that inhibit ovulation, hormone-releasing intrauterine devices, and copper intrauterine devices. The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not adequate methods of contraception. If required per local guidelines or regulations, locally recognized adequate methods of contraception and information about the reliability of abstinence will be described in the local Informed Consent Form. • For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use a condom, and agreement to refrain from donating sperm, as defined below: With a female partner of childbearing potential, men who are not surgically sterile must remain abstinent or use a condom plus an additional contraceptive method that together result in a failure rate of < 1% per year during the treatment period, for 90 days after the final dose of tiragolumab. Men must refrain from donating sperm during this same period. With a pregnant female partner, men must remain abstinent or use a condom during the treatment period for 90 days after the final dose of tiragolumab to avoid exposing the embryo. The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not adequate methods of contraception. If required per local guidelines or regulations, locally recognized adequate methods of contraception and information about the reliability of abstinence will be described in the local Informed Consent Form.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. Progression-free survival rate as measured by the proportion of patients free of progression after 12-weeks of treatment (PFS: time from administration of first treatment to tumor progression or death from any cause) according to RECIST1.1
2. Adverse events as measured according to CTCAE v5.0 and immune-related toxicity

Secondary endpoints 4

1. Response as measured by the objective response rate (ORR: complete responses or partial responses) according to iRECIST and RECIST1.1
2. Clinical benefit as measured by the clinical benefit rate (CBR) according to iRECIST and RECIST1.1
3. PFS measured by time to event
4. Overall survival (OS: time from therapy initiation to death from any cause)

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 3

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Het Nederlands Kanker Instituut-Antoni van Leeuwenhoek Ziekenhuis Stichting

Sponsor organisation

Het Nederlands Kanker Instituut-Antoni van Leeuwenhoek Ziekenhuis Stichting

Address

Plesmanlaan 121

City

Amsterdam

Postcode

1066 CX

Country

Netherlands

Scientific contact point

Organisation

Het Nederlands Kanker Instituut-Antoni van Leeuwenhoek Ziekenhuis Stichting

Contact name

Marleen Kok

Public contact point

Organisation

Het Nederlands Kanker Instituut-Antoni van Leeuwenhoek Ziekenhuis Stichting

Contact name

Marleen Kok

Locations

1 EU/EEA country · 1 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Application history

3 submissions — initial application plus substantial / non-substantial modifications