A Randomized Non-comparative Open-label Phase 1b/2 Study of Nadunolimab in Combination With Gemcitabine Plus Carboplatin in Patients With Advanced Triple Negative Breast Cancer. "TRIFOUR Study"

Plain English Summary

Nadunolimab in Combination With Gemcitabine Plus Carboplatin in Patients With Advanced Triple Negative Breast Cancer. is a Phase 2 clinical trial sponsored by Cantargia AB studying Triple Negative Breast Cancer. This study tests a new drug, nadunolimab, combined with standard chemotherapy (gemcitabine and carboplatin) for advanced triple-negative breast cancer. It is for patients with advanced triple-negative breast cancer that has spread or cannot be treated with curative intent. Participation involves receiving the study drug combination, with potential for biopsies to monitor the treatment's effects. Standard chemotherapy alone is the current alternative treatment for this condition. The trial aims to enroll 117 participants.

Official 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.

Who Can Participate

Here is what you need to know about eligibility for this trial. Patients must be 18 years or older with a confirmed diagnosis of triple-negative breast cancer. The cancer must be advanced, locally recurrent, inoperable, or metastatic. Patients should have received no more than one prior line of treatment for advanced disease. Good general health and adequate organ function are required. This trial is studying Triple Negative Breast Cancer, so participants generally need a confirmed diagnosis.

What They're Measuring

The primary outcome measures will determine how safe the new drug combination is and how well it shrinks tumors, indicating its potential effectiveness. The specific primary outcome measures are: Incidence rate of Dose Limiting Toxicity (DLT) within the first cycle of nadunolimab in combination with gemcitabine plus carboplatin (At the end of Cycle 1 (each cycle is 21 days)); Objective Response Rate (ORR) (Through study completion, an average of 58 months). These endpoints are how researchers determine whether the treatment is effective and will form the basis of any future regulatory submissions.

About This Phase

This trial is in Phase 2, which tests whether the treatment actually works against the target condition. Phase 2 trials involve 100-300 patients and continue to monitor safety while evaluating effectiveness. This phase often tests different dosages to find the optimal amount. About 33% of Phase 2 drugs advance to Phase 3. If successful, the treatment will move to large-scale Phase 3 trials needed for FDA approval.

Why This Trial Matters

This trial addresses a critical need for new therapies in advanced triple-negative breast cancer, an aggressive form of the disease with limited treatment options. Phase 2 success would typically lead to larger Phase 3 trials needed for regulatory approval. This research targets Triple Negative Breast Cancer, where improved treatment options are needed.

Investor Insight

This trial targets a specific subtype of breast cancer with high unmet need, potentially offering a new therapeutic option and representing an investment in novel oncology treatments. Phase 2 trials have approximately a 15-20% chance of eventually gaining FDA approval.

Is This Trial Right for Me?

Ask your doctor about the potential benefits and risks of nadunolimab, gemcitabine, and carboplatin. Understand the study schedule, including clinic visits, chemotherapy infusions, and any required biopsies. Discuss how participation might affect your daily life and any potential side effects. The trial is being conducted at 20 sites. Always discuss clinical trial participation with your healthcare provider before making any decisions. This information is for educational purposes only and is not medical advice.

AI-generated analysis for educational purposes only. This is not medical advice. Discuss clinical trial participation with your doctor. Data sourced from ClinicalTrials.gov.

Study Design

• Study Type: INTERVENTIONAL
• Allocation: RANDOMIZED
• Model: PARALLEL
• Masking: NONE
• Enrollment: 117 participants

Interventions

• DRUG: Carboplatin — Carboplatin Area Under the Curve (AUC) 2 mg/mL/min intravenous (IV) on days 1 and 8/15, in cycles of 3-4 weeks
• DRUG: Gemcitabine — Gemcitabine 1000 mg/m2 IV on days 1 and 8/15, in cycles of 3-4 weeks
• DRUG: Nadunolimab — 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.

Primary Outcomes

• Incidence rate of Dose Limiting Toxicity (DLT) within the first cycle of nadunolimab in combination with gemcitabine plus carboplatin (At the end of Cycle 1 (each cycle is 21 days))
• Objective Response Rate (ORR) (Through study completion, an average of 58 months)

Secondary Outcomes

• 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)

Full Eligibility Criteria

Inclusion Criteria: Patients are eligible to be enrolled in the study only if they meet all of the following criteria:

1. The patient has signed and dated the informed consent form (ICF) and it has been obtained before conducting any specific procedure for the study.
2. Female or male BC patients of ≥ 18 years of age.
3. 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.
4. 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).
5. 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).
6. Histologically confirmed TNBC that is either locally recurrent, inoperable and cannot be treated with curative intent or is metastatic:

   1. 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).
   2. 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.
   3. Patients are eligible for the study irrespectively of BRCA1/2 mutational status. It is not required to have the analysis performed before the study inclusion.
7. 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:

   1. 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.
   2. Prior therapy with immuno-checkpoint inhibitors (ICIs) either in the metastatic setting (as first-line therapy) or in the (neo)adjuvant setting is allowed.
   3. Previous treatment with platinum-derived agents in early-stage setting is allowed if the platinum-free interval is at least of 12 months.
   4. Prior therapy with PARP inhibitors is allowed.
8. Documented progressive disease (i.e. biopsy sample, pathology or imaging report) from the last treatment.
9. Eastern Cooperative Oncology Group (ECOG) Performance Status ≤ 1.
10. Patients must have at least one measurable lesion that can be accurately assessed at baseline and is suitable for repeated assessment by CT scan, MRI, plan X-ray or physical examination. Clinical lesions will only be considered measurable when they are superficial and ≥ 10mm in diameter as assessed using callipers (e.g. skin nodules). Patients with bone-only disease must have a lytic or mixed (lytic + blastic) lesion, which has not been previously irradiated and can be accurately assessed by CT scan/MRI according to RECIST version 1.1 (with a component of soft tissue mass).
11. Adequate organ and bone marrow function defined as follows:

    1. Absolute Neutrophil Count (ANC) ≥ 1.500/mm3 (1.5x109/L), without previous Granulocyte Colony-Stimulating Factor (G-CSF) within 2 weeks prior to the study treatment.
    2. Platelets ≥ 100.000/mm3 (100x109/L), without previous transfusion within 2 weeks prior to the study treatment.
    3. Hemoglobin ≥ 9 g/dL (90 g/L), without previous transfusion within 28 days before starting with the study treatment.
    4. Serum creatinine ≤ 1.5 x Upper Limit of Normal (ULN) or estimated creatinine clearance ≥ 60 mL/min as calculated using the Cockcroft-Gault formula.
    5. Total serum bilirubin ≤ 1.5 x ULN (≤ 3.0 x ULN if Gilbert´s disease).
    6. Aspartate aminotransferase (AST) and/or Alanine aminotransferase (ALT) ≤ 3.0 x ULN (≤ 5.0 x ULN if liver metastases present).
    7. Alkaline phosphatase ≤ 2.5 x ULN (≤ 5.0 x ULN if bone or liver metastases present).
12. Resolution of all acute toxic effects of prior anti-cancer therapy or surgical procedures to NCI CTCAE v5.0 Grade ≤ 1 (except alopecia or other toxicities not considered a safety risk for the patient at investigator's discretion). In case of immune-related toxicities, adequately resolved to Grade 1 or non-persistent Grade 2

Trial Locations

• Hospital Universitario Virgen de las Nieves, Granada, Andalusia, Spain
• Hospital Universitario Clinico San Cecilio, Granada, Andalusia, Spain
• Complejo Hospitalario de Jaén, Jaén, Andalusia, Spain
• Hospital Universitario Virgen De La Victoria, Málaga, Andalusia, Spain
• Hospital Universitario Virgen Macarena, Seville, Andalusia, Spain
• Hospital Universitario Virgen Del Rocío, Seville, Andalusia, Spain
• Hospital Clínico Universitario Lozano Blesa, Zaragoza, Aragon, Spain
• Onkologikoa, Donostia / San Sebastian, Basque Country, Spain
• Complejo Hospitalario Universitario de Albacete, Albacete, Castille-La Mancha, Spain
• Hospital Universitario de Toledo, Toledo, Castille-La Mancha, Spain
• ...and 10 more locations

Frequently Asked Questions

Related Conditions

• Triple Negative Breast Cancer
• Metastatic Breast Cancer
• Advanced Breast Cancer
• Hormone Receptor Negative Breast Cancer
• HER2 Negative Breast Cancer
• Chemotherapy
• Immunotherapy
• Oncology
• Cancer Treatment
• Clinical Trials

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