Durvalumab (MEDI4736) Plus Platinum-based Chemotherapy in Advanced LCNEC: a Pilot Phase II Study

  • STATUS
    Recruiting
  • End date
    Jan 1, 2025
  • participants needed
    22
  • sponsor
    Elizabeth Dudnik
Updated on 15 March 2022

Summary

PROTOCOL SYNOPSIS Clinical Protocol ESR-20-20907 Study Title: Durvalumab (MEDI4736) plus platinum-based chemotherapy in advanced large-cell neuroendocrine tumors of lung (LCNEC): a pilot phase II study Protocol Number: ESR-20-20907 Clinical Phase: phase II Study Duration: 30 months

Investigational Product(s) and Reference Therapy:

Investigational Product: Durvalumab (MEDI4736) Durvalumab concentrate for solution for infusion will be supplied in glass vials containing 500 mg durvalumab at a concentration of 50 mg/mL Reference Therapy: Cisplatin/Carboplatin+Etoposide Research Hypothesis

Primary hypothesis:

1.1 In patients with advanced treatment naive LCNEC, treatment with Durvalumab+ Cisplatin/Carboplatin+Etoposide is associated with 12-month PFS rate of at least 18%.

Secondary hypothesis:

1.2 In patients with advanced treatment naïve LCNEC, treatment with Durvalumab+ Cisplatin/Carboplatin+Etoposide is associated with ORR of 50%.

1.3 In patients with advanced treatment naïve LCNEC, treatment with Durvalumab+ Cisplatin/Carboplatin+Etoposide is associated with 12-months OS rate of at least 50%.

1.4 Incidence of grade ≥3 adverse events is less than 60%.

Exploratory hypothesis:

1.5 There is a positive correlation between the small-cell lung cancer-like molecular subtype and efficacy parameters (ORR, PFS, OS), and also between high TMB and efficacy parameters (ORR, PFS, OS) of treatment with Durvalumab+Cisplatin/Carboplatin+Etoposide in patients with advanced treatment naive LCNEC.

Objectives

Primary Objective:

1.1 To assess progression-free survival (PFS at 12 months, RECIST v. 1.1) with Durvalumab+ Cisplatin/Carboplatin+Etoposide in patients with advanced treatment-naive LCNEC.

Secondary Objectives:

1.2 To assess objective response rate (ORR at best response) according to Response Evaluation Criteria in Solid Tumors, v. 1.1 (RECIST v. 1.1) with Durvalumab+ Cisplatin/Carboplatin+Etoposide in patients with advanced treatment naive LCNEC.

1.3 To assess overall survival (OS at 12 months) with Durvalumab+ Cisplatin/Carboplatin+Etoposide in patients with advanced treatment-naive LCNEC.

1.4 To further evaluate the safety profile of Durvalumab+Cisplatin/Carboplatin+Etoposide in patients with advanced treatment naive LCNEC (CTCAE v. 5.0).

Exploratory Objectives:

1.5 To assess the predictive effect of tumor molecular subtype (small-cell lung cancer - like versus non-small cell lung cancer - like, assessed by NGS), tumor mutational burden (TMB, mut/Mb assessed by NGS) and PD-L1 (assessed by TPS - by IHC using 22C3 antibody) on ORR, PFS, and OS with Durvalumab+Cisplatin/Carboplatin+Etoposide in patients with advanced treatment-naive LCNEC.

Study Design:

  • Open-label non-randomized non-comparative single-center pilot phase 2 study
  • Response assessment: brain/chest/abdominal/pelvic CT scan every 8 weeks+-7 days
  • PFS, ORR - assessed by the board-certified radiology expert experienced in RECIST v. 1.1 evaluation; OS assessment

Number of Centers: single center Number of Patients: 22

Study Population:

Adult patients (aged ≥18 years) with histologically or cytologically documented advanced LCNEC (stage IV or stage III not eligible for definitive treatment) without prior systemic treatment for advanced disease.

Investigational Product(s), Dose and Mode of Administration:

The enrolled patients will receive IV durvalumab 1500 mg (administered on day 1 of each 21-day cycle), IV etoposide 100 mg/m² (administered on days 1-3 of each 21-day cycle), with investigator's choice of either IV carboplatin area under the curve 5 mg/mL per min or IV cisplatin 80 mg/m² (administered on day 1 of each 21-day cycle) for four cycles followed by maintenance IV durvalumab 1500 mg (administered on day 1 of each 28-day cycle).

Details
Condition Patients With Advanced Treatment Naive LCNEC
Treatment durvalumab
Clinical Study IdentifierNCT05262985
SponsorElizabeth Dudnik
Last Modified on15 March 2022

Eligibility

Yes No Not Sure

Inclusion Criteria

Patients with Grade ≥2 neuropathy will be evaluated on a case-by-case basis after consulting PI
Patients with irreversible toxicity not reasonably expected to be exacerbated by treatment with durvalumab may be included only after consulting PI
• Radiation therapy to the brain/lung within 1 week of study treatment
Prior radiation to other sites (excluding brain and lung) may be completed at any point prior to study treatment
Major surgery within 4 weeks of study treatment
Any concurrent chemotherapy (other than per protocol), immune check-point inhibitors, biologic, or hormonal therapy for cancer treatment
Current or prior use of immunosuppressive medication within 14 days before the first dose of durvalumab. The following are exceptions to this criterion
Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra
articular injection)
Systemic corticosteroids at physiologic doses not to exceed <<10 mg/day>> of prednisone or its equivalent
Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication)
Receipt of live attenuated vaccine within 30 days prior to the study treatment initiation
if enrolled, patients should not receive live vaccine whilst receiving study treatment and
up to 30 days after the last dose of study treatment
Body weight<30 kg
Active or prior documented autoimmune or inflammatory disorders (including
inflammatory bowel disease [e.g., colitis or Crohn's disease], systemic lupus
erythematosus, sarcoidosis, or Wegener syndrome [granulomatosis with polyangiitis
Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc]). The following are
exceptions to this criterion
Patients with vitiligo or alopecia
Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable on
hormone replacement
Any chronic skin condition that does not require systemic therapy
Patients without active disease in the last 5 years may be included on an
individual basis after consulting PI
Patients with celiac disease controlled by diet alone
Prior allogeneic bone marrow transplantation or solid organ transplant
History of active primary immunodeficiency
AIDS/HIV positivity (by history)
Active tuberculosis
Patients with active hepatitis B (HBV, chronic or acute; defined as having a positive
hepatitis B surface antigen (HBsAg) test at screening) or hepatitis C
Patients with past HBV infection or resolved HBV infection (defined as the
presence of hepatitis B core (HBc) antibody and absence of HBsAg) are eligible
Patients positive for hepatitis C virus (HCV) antibody are eligible only if
polymerase chain reaction is negative for HCV RNA
Any evidence of severe or uncontrolled concurrent condition that places patient at an
unacceptable risk from participation in the study/confounds the ability to interpret
study data, limits compliance with study requirements, substantially increases the
risk of incurring AEs, including but not limited to active infection, symptomatic
congestive heart failure, uncontrolled hypertension, unstable angina pectoris, chronic
diarrhea, interstitial lung disease
History of another primary malignancy except for
Malignancy treated with curative intent and with no known active disease ≥5 years
before the first dose of study treatment and of low potential risk for recurrence
Adequately treated non-melanoma skin cancer or lentigo maligna without evidence
of disease
Adequately treated carcinoma in situ without evidence of disease
Contraindication for CT
Known allergy or hypersensitivity to any of the study drugs or any of the study drug
excipients
Female patients who are pregnant or breastfeeding or male or female patients of
reproductive potential who are not willing to employ effective birth control from
screening to 90 days after the last dose of durvalumab monotherapy
Inability to sign the informed consent form
Concurrent enrolment in another clinical study unless it is an observational
(non-interventional) clinical study or during the follow-up period of an
interventional study more than 4 weeks since last study treatment
Prior randomization or treatment in a previous durvalumab clinical study regardless of
treatment arm assignment

Exclusion Criteria

Exclusion Criteria
Carcinomatous meningitis or history of carcinomatous meningitis
Prior treatment with an anti-PD-1/anti-PD-L1 agent/chemotherapy
Patients who have received prior anti-PD-1/anti-PD-L1 agent/platinum-based
chemotherapy as neo-adjuvant or adjuvant therapy with curative intent for non-
metastatic disease must have experienced a disease-free interval of at least 6
months since the last anti-PD-1/anti-PD-L1 agent/chemotherapy administration
• Patients who have received prior anti-PD-1/anti-PD-L1 agent
Must not have experienced a toxicity that led to permanent discontinuation of prior immunotherapy
All AEs while receiving prior immunotherapy must have completely resolved or resolved to baseline prior to screening for this study
Must not have experienced a ≥Grade 3 immune related AE or an immune related neurologic or ocular AE of any grade while receiving prior immunotherapy; patients with endocrine AE of ≤Grade 2 are permitted to enrol if they are stably maintained on appropriate replacement therapy and are asymptomatic
Must not have required the use of additional immunosuppression other than corticosteroids for the management of an AE, not have experienced recurrence of an AE if re-challenged, and not currently require maintenance doses of > 10 mg prednisone or equivalent per day
• Any unresolved toxicity ≥Grade 2 from previous anticancer therapy with the
exception of alopecia, vitiligo, and the laboratory values defined in the
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