Threshold (THLD) starà guardando ai risultati di Abraxane con un certo interesse. Anche io.

Patients on a combination of Abraxane and gemcitabine, another chemotherapy, lived for a median 8.5 months, compared to 6.7 months for those that received gemcitabine alone. That means that survival was extended by 1.8 months, or 7.7 weeks, for an average patient. According to surveys run by Mark Schoenebaum at ISI Group, investors had expected a survival extension of 7.6 weeks to 7.8 weeks.[…]

Other measures of the survival figures are more dramatic – although also disheartening, because they show what a rapid killer the disease is. There was a 28% reduction in the risk of death during the trial for patients who got Abraxane. At the end of the year, 35% of those that received Abraxane were still alive, compared to 22% of those that received gemcitabine. At the end of two years, those numbers were 9% and 4%. The clinical trial followed a total of 842 patients until 608 of them had died in order to get statistical power.

I pazienti ai quali è stato somministrato Abraxane e gemcitabina hanno ottenuto una sopravvivenza globale media di 8,5 mesi contro i 6,7 di quanti hanno ricevuto solo gemcitabina con un beneficio di 7,7 settimane, in linea con quanto atteso. Sapevamo che lo studio era andato bene visto che Celgene di questo ci aveva informato, mancavano i numeri.

Bene. Quando dicevo che i dati di TH 302 di Threshold erano impressionanti (inizialmente riferendomi alla progressione libera da malattia), mi riferivo anche a questo.

The study found that patients who received 340 mg/m2 TH-302 plus gemcitabine experienced a median overall survival of 9.2 months compared with 6.9 months in patients who received gemcitabine alone (hazard ratio [HR] = 0.955; 95% confidence interval [CI], 0.67-1.37, P = .800). Patients who received 240 mg/m2 TH-302 plus gemcitabine experienced a median overall survival period of 8.7 months compared with the gemcitabine alone arm (HR = 0.960; 95% CI, 0.67-1.38, P = .827).

Possiamo discutere sul fatto che il dato di Threshold rispetto a quello di Celgene non è statisticamente significativo, anche se vi avevo già detto che lo studio non aveva la potenza sufficiente per mostrare una simile evidenza, e che l’Hazard Ratio di Abraxane sia 0,72 vs 0,95 di TH 302 che migliora solo leggermente se consideriamo che i pazienti del braccio di controllo potevano effettuare il cross-over verso il braccio attivo, peggiorando i dati di Threshold, ma il valore dei due farmaci non mi pare tanto differente quanto ci si aspettasse, a detta di molti key opinion leader. Anzi.

Inizio col dire che qui abbiamo dati relativi al gruppo di controllo piuttosto simili, il che ci consente di poter confrontare l’efficacia di Abraxane e di TH 302 in modo piuttosto interessante. Abbiamo i 6,7 mesi del controllo di Abraxane ed i 6,9 di TH 302, numeri in linea con quanto atteso e simili fra loro.

Questi i criteri di inclusione per TH 302:

Inclusion Criteria:

1. At least 18 years of age
2. Ability to understand the purposes and risks of the study and has signed a written informed consent form approved by the investigator’s IRB/Ethics Committee
3. Locally advanced unresectable or metastatic pancreatic ductal adenocarcinoma proven either by histology or cytology previously untreated with chemotherapy or systemic therapy other than:
   • Radiosensitizing doses of 5-fluorouracil;
   • Radiosensitizing doses of gemcitabine if relapse occurred at least 6 months after completion of gemcitabine;
   • Neoadjuvant chemotherapy if relapse occurred at least 6 months after surgical resection;
   • Adjuvant chemotherapy if relapse occurred at least 6 months after completion of adjuvant chemotherapy.
4. Measurable disease by RECIST 1.1 criteria (at least one target lesion outside of previous radiation fields)
5. Documentation of disease progression since any prior therapy
6. ECOG performance status of 0 or 1
7. Life expectancy of at least 3 months
8. Acceptable liver function:
   1. Bilirubin less than or equal to 1.5 times upper limit of normal
   2. AST (SGOT) and ALT (SGPT) less than or equal to 2.5 times upper limit of normal (ULN); if liver metastases are present, then less than or equal to 5 times ULN is allowed
9. Acceptable renal function:a. Serum creatinine less than or equal to ULN
10. Acceptable hematologic status (without hematologic support):
    1. ANC greater than or equal to 1500 cells/μL
    2. Platelet count greater than or equal to 100,000/μL
    3. Hemoglobin greater than or equal to 9.0 g/dL
11. All women of childbearing potential must have a negative serum pregnancy test and male and female subjects must agree to use effective means of contraception (surgical sterilization or the use or barrier contraception with either a condom or diaphragm in conjunction with spermicidal gel or an IUD) with their partner from entry into the study through 6 months after the last dose

Questi per invece quelli per Abraxane:

A patient will be eligible for inclusion in this study only if all of the following criteria are met:

1. Patient has definitive histologically or cytologically confirmed metastatic adenocarcinoma of the pancreas. The definitive diagnosis of metastatic pancreatic adenocarcinoma will be made by integrating the histopathological data within the context of the clinical and radiographic data. Patients with islet cell neoplasms are excluded.
2. Initial diagnosis of metastatic disease must have occurred ≤6 weeks prior to randomization in the study.
3. Patient has one or more metastatic tumors measurable by CT scan (or MRI, if patient is allergic to CT contrast media).
4. Male or non-pregnant and non-lactating female, and ≥ 18 years of age. If a female patient is of child-bearing potential, as evidenced by regular menstrual periods, she must have a negative serum pregnancy test (β-hCG) documented 72 hours prior to the first administration of study drug.If sexually active, the patient must agree to use contraception considered adequate and appropriate by the Investigator during the period of administration of study drug. In addition, male and female patients must utilize contraception after the end of treatment as recommended in the product’s Summary of Product Characteristics or Prescribing Information provided in the study manual.
5. Patients must have received no previous radiotherapy, surgery, chemotherapy or investigational therapy for the treatment of metastatic disease. Prior treatment with 5-FU or gemcitabine administered as a radiation sensitizer in the adjuvant setting is allowed, provided at least 6 months have elapsed since completion of the last dose and no lingering toxicities are present. Patients having received cytotoxic doses of gemcitabine or any other chemotherapy in the adjuvant setting are not eligible for this study.
6. Patient has adequate biological parameters as demonstrated by the following blood counts at Baseline (obtained ≤14 days prior to randomization):Absolute neutrophil count (ANC) ≥ 1.5 × 109/L; Platelet count ≥ 100,000/mm3 (100 × 109/L); Hemoglobin (Hgb) ≥ 9 g/dL.
7. Patient has the following blood chemistry levels at Baseline (obtained ≤14 days prior to randomization):AST (SGOT), ALT (SGPT) ≤ 2.5 × upper limit of normal range (ULN), unless liver metastases are clearly present, then ≤ 5 × ULN is allowed Total bilirubin ≤ ULN Serum creatinine within normal limits or calculated clearance ≥ 60 mL/min/1.73 m2 for patients with serum creatinine levels above or below the institutional normal value. If using creatinine clearance, actual body weight should be used for calculating creatinine clearance (e.g., using the Cockroft-Gault formula). For patients with a Body Mass Index (BMI) >30 kg/m2, lean body weight should be used instead.
8. Patient has acceptable coagulation studies (obtained ≤14 days prior to randomization) as demonstrated by prothrombin time (PT) and partial thromboplastin time (PTT) within normal limits (± 15%). (See also Section 6.2 for Baseline PT/PTT analysis).
9. Patient has no clinically significant abnormalities in urinalysis results (obtained ≤14 days prior to randomization).
10. Patient has a Karnofsky performance status (KPS) ≥ 70. Two observers will be required to assess KPS. If discrepant, the one with the lowest assessment will be considered true.
11. Patients should be asymptomatic for jaundice prior to Day 1. Significant or symptomatic amounts of ascites should be drained prior to Day 1. Pain symptoms should be stable and should not require modifications in analgesic management prior to Day 1.
12. Patient has been informed about the nature of the study, and has agreed to participate in the study, and signed the Informed Consent Form (ICF) prior to participation in any study-related activities.

Ora, nessuno si aspetta che in fase 3 TH 302 riproduca esattamente lo stesso tipo di risultato della fase 2, nessun farmaco lo fa… ma tutte le persone che fino a non molte ore fa davano Threshold immolata sull’altare di Abraxane oggi probabilmente si stanno chiedendo se la loro convinzione fosse esatta.

Abraxane ha il grande vantaggio di essere impiegato off-label e di avere già un consenso enorme, questo è chiaro. Questo però, agli azionisti di Threshold potrebbe anche non interessare…