Nadunolimab in Combination with Gemcitabine Plus Carboplatin in Patients with Advanced Triple Negative Breast Cancer.

NCT05181462 | Active Not Recruiting Phase 1

• 2 other identifiers: CAN04CLIN0052021-003402-46
• Study Type: interventional
• Target: 117
• Locations: 1 country
• Sites: 23

Brief Summary

Triple negative breast cancer (TNBC) represents approximately 15% of all breast cancers (BC) worldwide. The term triple negative means that tumor growth is not stimulated by the hormones estrogen and progesterone, nor by the HER2 protein, so unlike other types of BC, TNBC, which is an aggressive form of BC, does not have specific effective therapies available being the least common form of BC and the most difficult to treat. Advanced or metastatic TNBC is treated with combinations of platinum-based chemotherapy with taxanes or gemcitabine with a 5-year survival rate of 12%. Recent studies have shown that TNBC expresses Interleukin 1 Receptor Accessory Protein (IL1RAP) at higher levels than other forms of BC. Nadunolimab is a fully humanized monoclonal antibody that blocks the signals that occur within the cell produced by IL1RAP protein, thereby impairing the cancer cells' ability to secrete tumor stimulating substances, in turn reducing the tumor, inflammation and tumor progression. On the other hand, it is an antibody designed to activate the immune system to fight cancer cells. This clinical trial is divided into two phases, phase Ib in which it is expected to include up to 15 patients and phase II in which it is expected to include 102 patients. The main purpose of phase Ib is to ensure that the combination of nadunolimab plus chemotherapy (gemcitabine plus carboplatin) is safe and determine the highest dose of nadunolimab that can be given safely without causing serious side effects. If the pre-specified objectives in this part are achieved, the trial will be expanded to a randomized phase II, to evaluate the efficacy of the combination of nadunolimab plus gemcitabine plus carboplatin, compared to a control group that will receive gemcitabine plus carboplatin only.

Conditions

Triple Negative Breast Cancer

Keywords

Unresectable locally advanced; Metastatic triple negative breast cancer; Nadunolimab

Outcome Measures

Primary Outcomes (2)

• Incidence rate of Dose Limiting Toxicity (DLT) within the first cycle of nadunolimab in combination with gemcitabine plus carboplatin

  DLT is defined according to the NCI-CTCAE version 5.0 as any of the following events considered by investigator to be related to investigational treatment: 1. Grade (G) 5 Treatment Emergent AE 2. G ≥ 3 neutropenia + fever and/or infection (single temp. \> 38.3°C or sustained temp. ≥ 38°C \>1 hour) 3. G 4 neutropenia \> 7 days 4. G 4 thrombocytopenia \> 3 days 5. G ≥ 3 thrombocytopenia \> 7 days or accompanied by G 2 bleeding or platelet transfusion 6. Delay in the initiation of Cycle 2 \> 14 days from the calculated start date due to a lack of adequate recovery of treatment-related hematological or non-hematological toxicity 7. G ≥ 3 AE with permanent discontinuation of any of the study drugs 8. Elevations of bilirubin and transaminases meeting Hy's Law criteria 9. G 4 laboratory abnormalities discussed with the Medical Coordinators, Sponsor and GEICAM 10. G ≥ 3 non-hematological toxicity 11. G 2 toxicity considered a dose limiting

  At the end of Cycle 1 (each cycle is 21 days)

• Objective Response Rate (ORR)

  Tumor response is assessed according to Response Evaluation Criteria for Solid Tumors (RECIST) version 1.1 as per investigators' assessment. ORR is defined as the rate of Complete Response (CR) plus Partial Response (PR) according to RECIST version 1.1, out of the patients who receive at least one dose of treatment and have measurable disease. These results will be calibrated against the ORR in the control arm.

  Through study completion, an average of 58 months

Secondary Outcomes (18)

• Clinical Benefit Rate (CBR)

  Through study completion, an average of 58 months

• Disease Control Rate (DCR)

  Through study completion, an average of 58 months

• Duration of Response (DoR)

  Through study completion, an average of 58 months

• Progression-Free Survival (PFS)

  Through study completion, an average of 58 months

• Proportion of patients free of PD at 6 and 12 months

  Up to 12 months

Study Arms (3)

Phase Ib: Single-arm (dose-escalation 3+3 design).

EXPERIMENTAL

* Carboplatin Area Under the Curve (AUC) 2 mg/mL/min intravenous (IV) on days 1 and 8, every 3-week cycles. * Gemcitabine 1000 mg/m2 IV on days 1 and 8, every 3-week cycles. * Nadunolimab escalation (DL -1: 0.5 mg/Kg, DL 1: 1 mg/kg, DL 2: 2.5 mg/kg), DL 3: 5 mg/kg IV on days 1 and 8, every 3-week cycles.

Drug: Carboplatin; Drug: Gemcitabine; Drug: Nadunolimab

Phase II: Randomized 1:1, non-comparative, open-label.Patients randomized to arm A

EXPERIMENTAL

* Carboplatin AUC 2 mg/mL/min IV on days 1 and 8, every 3-week cycles. * Gemcitabine 1000 mg/m2 IV on days 1 and 8, every 3-week cycles. * Nadunolimab Recommended Phase II Dose (RP2D) mg/kg IV on days 1 and 8, every 3-week cycles

Drug: Carboplatin; Drug: Gemcitabine; Drug: Nadunolimab

Phase II: Randomized 1:1, non-comparative, open-label.Patients randomized to arm B

ACTIVE COMPARATOR

* Carboplatin AUC 2 mg/mL/min IV on days 1 and 8, every 3-week cycles. * Gemcitabine 1000 mg/m2 IV on days 1 and 8, every 3-week cycles.

Drug: Carboplatin; Drug: Gemcitabine

Interventions

Carboplatin DRUG

Carboplatin Area Under the Curve (AUC) 2 mg/mL/min intravenous (IV) on days 1 and 8/15, in cycles of 3-4 weeks

Phase II: Randomized 1:1, non-comparative, open-label.Patients randomized to arm A; Phase II: Randomized 1:1, non-comparative, open-label.Patients randomized to arm B; Phase Ib: Single-arm (dose-escalation 3+3 design).

Gemcitabine DRUG

Gemcitabine 1000 mg/m2 IV on days 1 and 8/15, in cycles of 3-4 weeks

Phase II: Randomized 1:1, non-comparative, open-label.Patients randomized to arm A; Phase II: Randomized 1:1, non-comparative, open-label.Patients randomized to arm B; Phase Ib: Single-arm (dose-escalation 3+3 design).

Nadunolimab DRUG

Nadunolimab escalation (DL -1: 0.5 mg/Kg, DL 1: 1 mg/kg, DL 2: 2.5 mg/kg), DL 3: 5 mg/kg IV on days 1 and 8/15, in cycles of 3-4 weeks.

Also known as: CAN04

Phase II: Randomized 1:1, non-comparative, open-label.Patients randomized to arm A; Phase Ib: Single-arm (dose-escalation 3+3 design).

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• The patient has signed and dated the informed consent form (ICF) and it has been obtained before conducting any specific procedure for the study.
• Female or male BC patients of ≥ 18 years of age.
• Permission to access archived tumor tissue sample (either from primary breast tumor or a metastatic lesion, preferably the most recent one) for biomarker analysis. Not having archived tissue is not a reason to exclude the patient from enrollment.
• Paired tumor biopsies, pre-treatment and on-treatment, for pharmacodynamic analysis are not compulsory and will be obtained as per investigator judgement and patient decision. However, patients and investigators are encouraged to obtain them if the patient has easily accessible disease like skin or superficial lymph nodes. Ideally, the same lesion (always in the same organ) should be biopsied before treatment and on treatment whenever possible. It is allowed to use archived biopsies as pre-treatment samples, obtained after ending the previous systemic treatment).
• The lesion accessible for biopsy may not be the only target lesion and should not be located in a previously irradiated field (unless this index lesion has PD ≥ 20% post-radiation).
• Histologically confirmed TNBC that is either locally recurrent, inoperable and cannot be treated with curative intent or is metastatic:
• Documented Hormone Receptor (HR) negative BC based on local laboratory determination on the most recent tumor biopsy. HR negative defined as \< 1% positive cells by immunohistochemistry (IHC) for estrogen receptor (ER) and progesterone receptor (PgR).
• Documented Human Epidermal Growth Factor Receptor 2 (HER2) negative BC based on local laboratory determination on the most recent tumor biopsy. HER2 negative tumor is determined according to recommendations of the applicable American Society of Clinical Oncology (ASCO)/ College of American Pathologists (CAP) guidelines available.
• Patients should be eligible to receive gemcitabine and carboplatin as the following line of therapy. No more than 1 previous line of systemic therapy for the advanced disease is allowed:
• Those patients with PD during or within 6 months after completing the (neo)adjuvant treatment are allowed to be included in the study and are considered for second-line group of patients.
• Prior therapy with immuno-checkpoint inhibitors (ICIs) either in the metastatic setting (as first-line therapy) or in the (neo)adjuvant setting is allowed.
• Previous treatment with platinum-derived agents in early-stage setting is allowed if the platinum-free interval is at least of 12 months.
• Prior therapy with PARP inhibitors is allowed.
• Documented progressive disease (i.e. biopsy sample, pathology or imaging report) from the last treatment.
• Eastern Cooperative Oncology Group (ECOG) Performance Status ≤ 1.

You may not qualify if:

• Patient has received extended field radiotherapy ≤ 4 weeks before the start of treatment (≤ 2 weeks for limited field radiation for palliation), and who has not recovered to ≤ Grade 1, according to NCI CTCAE v5.0, from related AEs of such therapy (except for alopecia).
• Treatment with systemic anticancer treatments, investigational products, or major surgery within 4 weeks before the first dose of study drug or 5 half-lives, whichever is shorter. Patients should have recovered from previous treatment toxicity to ≤ Grade 1 (except alopecia and peripheral neuropathy).
• No prior treatment with an anthracycline and a taxane unless contraindicated or not considered the most suitable treatment option (e.g. in the de novo metastatic setting) according to physician's opinion.
• Significant cardiovascular disease, such as New York Heart Association (NYHA) cardiac disease (Class II or greater), myocardial infarction, or cerebrovascular accident within 3 months prior to randomization, unstable arrhythmias, or unstable angina. Patients with a known left ventricular ejection fraction (LVEF) \< 50% will be excluded.
• Patients with known coronary artery disease or congestive heart failure (CHF) not meeting the above criteria, must be on a stable medical regimen that is optimized in the opinion of the treating physician, in consultation with a cardiologist if appropriate.
• Presence of an abnormal ECG that is clinically significant in the investigator's opinion, including complete left bundle branch block, second or third-degree heart block, or QT interval corrected using Fridericia's formula (QTcF) \> 480 ms demonstrated by at least two consecutive ECGs.
• Patients with uncontrolled brain metastases; however, patients who have been previously treated with surgery, whole-brain radiation, and/or stereotactic radiosurgery and are considered controlled (with ≤ 10 mg/day of prednisone or equivalent) at the time of receiving the first dose of nadunolimab are allowed. For asymptomatic patients, screening brain imaging is not required.
• Spinal cord compression not definitively treated with surgery and/or radiation, or previously diagnosed and treated spinal cord compression without evidence that disease has been clinically stable for \> 2 weeks prior to enrolment.
• Severe (Grade 3) infection requiring oral or IV antibiotics within 4 weeks prior to enrolment, including but not limited to hospitalization for complications of infection, bacteremia, or pneumonia. Patients receiving prophylactic antibiotics (e.g., to prevent a urinary tract infection or chronic obstructive pulmonary disease exacerbation) are eligible for the study.
• Positive hepatitis B surface antigen (HBsAg) test at screening: Total hepatitis B core antibody (HBcAb) test at screning must be negative. If HBsAg and HBcAb are positive, hepatitis B virus (HBV) DNA test at screening should be performed and if patient does not have viral load, patient can be enrolled into the study.
• Positive hepatitis C virus (HCV) antibody test at screening: if 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.
• Pregnant or lactating or intending to become pregnant during or within 6 months after the last dose of study treatment.
• Known hypersensitivity or allergy to any component of the nadunolimab, carboplatin or gemcitabine drug formulations, and known hypersensitivity to platinum-containing compounds.
• Patients who receive a live vaccination, etanercept, or other Tumor necrosis factor (TNF)-alpha inhibitors just prior to participation in this study (within 28 days of first study drug administration).
• Patients with a history of autoimmune disease requiring systemic immunosuppressive therapy (daily prednisone equivalent doses \> 10 mg/day). Patients with autoimmune diseases and without systemic therapies are allowed.

Sponsors & Collaborators

• Cantargia AB: lead
• Spanish Breast Cancer Research Group: collaborator

Study Sites (23)

Hospital Universitario Virgen de las Nieves

Granada, Andalusia, 18014, Spain

Location

Hospital Universitario Clinico San Cecilio

Granada, Andalusia, 18016, Spain

Location

Complejo Hospitalario de Jaén

Jaén, Andalusia, 23007, Spain

Location

Hospital Universitario Virgen De La Victoria

Málaga, Andalusia, 29010, Spain

Location

Hospital Universitario Virgen Macarena

Seville, Andalusia, 41009, Spain

Location

Hospital Universitario Virgen Del Rocío

Seville, Andalusia, 41013, Spain

Location

Hospital Clínico Universitario Lozano Blesa

Zaragoza, Aragon, 50009, Spain

Location

Onkologikoa

Donostia / San Sebastian, Basque Country, 20014, Spain

Location

Complejo Hospitalario Universitario de Albacete

Albacete, Castille-La Mancha, 02006, Spain

Location

Hospital Universitario de Toledo

Toledo, Castille-La Mancha, 45007, Spain

Location

Hospital del Mar

Barcelona, Catalonia, 08003, Spain

Location

Hospital Clinic de Barcelona

Barcelona, Catalonia, 08036, Spain

Location

ICO Institut Catalá d'Oncologia de L´Hospitalet

Hospitalet de Llobregat, Barcelona, Catalonia, 08908, Spain

Location

Hospital Universitario Arnau de Vilanova Lleida

Lleida, Catalonia, 25198, Spain

Location

Complejo Hospitalario Universitario A Coruña

A Coruña, Galicia, 15006, Spain

Location

Hospital Universitario Lucus Augusti

Lugo, Galicia, 27003, Spain

Location

Hospital Materno Infantil de Gran Canaria

Las Palmas de Gran Canaria, Las Palmas, 35016, Spain

Location

Hospital Universitario Gregorio Marañón

Madrid, Madrid, 28007, Spain

Location

Hospital Clínico San Carlos

Madrid, Madrid, 28040, Spain

Location

Hospital Universitario 12 de Octubre

Madrid, Madrid, 28041, Spain

Location

Clínica Universidad de Navarra

Pamplona, Navarre, 31008, Spain

Location

Hospital Universitario San Juan de Alicante

Alicante, Valencia, 03550, Spain

Location

Fundación Instituto Valenciano de Oncología

Valencia, Valencia, 46009, Spain

Location

Related Links

• Description GEICAM is a Spanish Breast Cancer Research Group

MeSH Terms

Conditions

Triple Negative Breast Neoplasms

Interventions

Carboplatin; Gemcitabine

Condition Hierarchy (Ancestors)

Breast Neoplasms; Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Coordination Complexes; Organic Chemicals; Heterocyclic Compounds; Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring

Study Officials

• Chief Investigator

  Hospital General Universitario Gregorio

  STUDY DIRECTOR

• Chief Investigator

  Clínica Universitaria de Navarra

  STUDY DIRECTOR

• Chief Investigator

  Instituto de Investigación Sanitaria (IIS) Biodonostia - OSI

  STUDY DIRECTOR

• Chief Medical Officer

  Cantargia AB

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: Phase Ib: Single-arm (dose-escalation 3+3 design). * Nadunolimab escalation (Dose Level (DL) -1: 0.5 mg/Kg, DL 1: 1 mg/kg, DL 2: 2.5 mg/kg), DL 3: 5 mg/kg IV on days 1 and 8/15, in cycles of 3-4 weeks. * Gemcitabine 1000 mg/m2 IV on days 1 and 8/15, in cycles of 3-4 weeks. * Carboplatin Area Under the Curve (AUC) 2 mg/mL/min intravenous (IV) on days 1 and 8/15, in cycles of 3-4 weeks. Phase II: Randomized 1:1, non-comparative, open-label. Patients randomized to arm A will receive: * Nadunolimab Recommended Phase II Dose (RP2D) mg/kg IV on days 1 and 8/15, in cycles of 3-4 weeks. * Gemcitabine 1000 mg/m2 IV on days 1 and 8/15, in cycles of 3-4 weeks. * Carboplatin AUC 2 mg/mL/min IV on days 1 and 8/15, in cycles of 3-4 weeks. Patients randomized to arm B will receive: * Gemcitabine 1000 mg/m2 IV on days 1 and 8/15, in cycles of 3-4 weeks. * Carboplatin AUC 2 mg/mL/min IV on days 1 and 8/15, in cycles of 3-4 weeks.

Study Record Dates

• First Submitted: December 1, 2021
• First Posted: January 6, 2022
• Study Start: January 11, 2022
• Primary Completion: June 15, 2025
• Study Completion (Estimated): August 1, 2026
• Last Updated: March 14, 2025

Record last verified: 2025-03

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL
• Time Frame: When results will be analyzed following the Statistical Analysis Plan (SAP).
• Access Criteria: The results will be published. Every efforts Will be made to have open-access manuscripts.

Locations

ES (23)