Personalized Neoantigen Vaccine in Combination With Durvalumab (MEDI4736) and Tremelimumab in Extensive Stage Small Cell Lung Cancer

Overview

The investigators hypothesize that a personalized neoantigen vaccine combined with durvalumab and tremelimumab will improve the progression free survival of patients with extensive state small cell lung cancer (ES-SCLC) at six months following study therapy.

Full Title of Study: “Phase II Study of a Personalized Neoantigen Vaccine in Combination With Durvalumab (MEDI4736) and Tremelimumab in Extensive Stage Small Cell Lung Cancer”

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Randomized
    • Intervention Model: Parallel Assignment
    • Primary Purpose: Treatment
    • Masking: None (Open Label)
  • Study Primary Completion Date: October 31, 2022

Interventions

  • Biological: Neoantigen DNA vaccine
    • All study injections will be given intramuscularly using an integrated electroporation device (TDS-IM system, Ichor Medical Systems). At each vaccination time point, patients will receive two injections of the neoantigen DNA vaccine, one injection into each deltoid or lateralis.
  • Drug: Durvalumab
    • -Supplied by AstraZeneca/MedImmune
  • Drug: Tremelimumab
    • -Supplied by AstraZeneca/MedImmune
  • Device: TDS-IM v1.0 System
    • -Integrated electroporation administration system
  • Procedure: Peripheral blood draws
    • -Pre-treatment, Week 3 (before Cycle 2 chemotherapy), Week 6 (before Cycle 3 chemotherapy), Week 9 (before Cycle 4 chemotherapy), Day 1 (vaccine day 1 / C1D1 of durvalumab + tremelimumab), Day 29 (vaccine day 1 / C2D1 of durvalumab + tremelimumab), Day 85 (vaccine day 4 / C4D1 of durvalumab + tremelimumab), Day 141 (vaccine day 6 / C2D1 of durvalumab monotherapy)

Arms, Groups and Cohorts

  • Experimental: Arm A: neoantigen DNA vaccine+durvalumab+tremelimumab
    • Patients will receive durvalumab (1500mg Q3W) in combination with standard of care carboplatin and etoposide for a total of 4 cycles given every 3 weeks Beginning 4 weeks following Cycle 4 of carboplatin/etoposide/durvalumab, patients on Arm A will then receive four cycles of durvalumab 1500 mg and tremelimumab 75 mg with the polyepitope neoantigen DNA vaccine, with each cycle given every 4 weeks. Patients on Arm A will then receive an additional two doses of vaccine given with 1500 mg of durvalumab q4wk (to complete a series of 6 total doses of vaccine). Patients on Arm A are then eligible to receive durvalumab every 4 weeks to complete a total course of therapy of 2 years. In the event that after biopsy a vaccine cannot be produced for a patient randomized to Arm A, that patient will be eligible to cross over to Arm B.
  • Active Comparator: Arm B: durvalumab+tremelimumab
    • Patients will receive durvalumab (1500mg Q3W) in combination with standard of care carboplatin and etoposide for a total of 4 cycles given every 3 weeks. Beginning 4 weeks following Cycle 4 of carboplatin/etoposide/durvalumab,patients will receive durvalumab (1500mg Q4W) in combination with tremelimumab (75 mg IV Q4W) for up to 4 doses/cycles each, followed by durvalumab 1500mg every 4 weeks for a maximum of 2 years

Clinical Trial Outcome Measures

Primary Measures

  • Safety and tolerability of the combination of durvalumab and tremelimumab with or without neoantigen vaccine as measured by number of participants experiencing adverse events
    • Time Frame: Through 90 days after completion of treatment (estimated to be 2 years and 3 months)
    • -Safety and tolerability will be measured by National Cancer Institute Common Terminology Criteria (NCI CTCAE) v 5.0
  • Feasibility of combining durvalumab and tremelimumab with a neoantigen vaccine as measured by the number of participants in Arm A that had a vaccine produced for them
    • Time Frame: Completion of enrollment of Arm A (estimated to be 2 years)
    • -Feasibility is defined as the ability to produce a vaccine for 80% of patients enrolled on Arm A of this study.

Secondary Measures

  • Progression-free survival (PFS)
    • Time Frame: 12 months
    • PFS is defined as the duration of time from start of treatment to time of progression or death, whichever occurs first. Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progressions).
  • Objective response rate (ORR)
    • Time Frame: Through completion of treatment (estimated to be 2 years)
    • ORR is the proportion of participants with either a complete response or partial response Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. Disappearance of all non-target lesions and normalization of tumor marker level. Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.
  • Response conversion rate
    • Time Frame: Through completion of treatment (estimated to be 2 years)
    • -The response conversion rate is defined as the proportion of patients who improve in RECIST v1.1 category subsequent to vaccination.
  • Duration of response (DOR)
    • Time Frame: Through completion of treatment (estimated to be 2 years)
    • -The duration of response is measured from the time measurement criteria are met for CR or PR (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented (taking as reference for progressive disease the smallest measurements recorded since the treatment started).
  • Overall survival (OS)
    • Time Frame: Through completion of follow-up (estimated to be 4 years)

Participating in This Clinical Trial

Inclusion Criteria

  • Histologically or cytologically confirmed extensive stage small cell lung cancer.
  • Measurable disease defined as lesions that can be accurately measured in at least one dimension (longest diameter to be recorded) as ≥ 10 mm with CT scan, as ≥ 20 mm by chest x-ray, or ≥ 10 mm with calipers by clinical exam.
  • Disease must be able to be biopsied.
  • At least 18 years of age.
  • ECOG performance status ≤ 1
  • Life expectancy of at least 12 weeks.
  • Body weight > 30 kg.
  • Adequate normal organ and marrow function as defined below:
  • Hemoglobin ≥ 9.0 g/dL
  • Absolute neutrophil count ≥ 1000 K/cumm
  • Platelet count ≥ 75,000 K/cumm
  • Serum bilirubin ≤ 1.5 x institutional upper limit of normal (IULN)
  • AST (SGOT)/ALT (SGPT) ≤ 2.5 x IULN unless liver metastases are present, in which case it must be ≤ 5 x IULN
  • Measured creatinine clearance > 40 mL/min or calculated creatinine clearance > 40 mL/min by the Cockcroft-Gault formula or by 24-hour urine collection for determination of creatinine clearance
  • Adequate cardiac function defined as QTcF < 470 ms on 12-lead EKG.
  • Evidence of post-menopausal status or negative urinary or serum pregnancy test for female pre-menopausal patients. Women will be considered post-menopausal if they have been amenorrheic for 12 months without an alternative medical cause. The following age-specific requirements apply:
  • Women < 50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of exogenous hormonal treatments and if they have luteinizing hormone and follicle-stimulating hormone levels in the post-menopausal range for the institution or underwent surgical sterilization (bilateral oophorectomy or hysterectomy).
  • Women ≥ 50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of all exogenous hormonal treatments, had radiation-induced menopause with last menses > 1 year ago, had chemotherapy-induced menopause with last menses > 1 year ago, or underwent surgical sterilization (bilateral oophorectomy, bilateral salpingectomy, or hysterectomy):
  • Male and female patients of reproductive potential must be willing to employ effective birth control from screening to 90 days after the last dose of durvalumab monotherapy or 180 days after the last dose of durvalumab + tremelimumab combination therapy.
  • Ability to understand and willingness to sign an IRB approved written informed consent document (or that of legally authorized representative, if applicable). This includes consent for tumor/normal exome sequencing and dbGaP-based data sharing.

Exclusion Criteria

  • Prior treatment with a PD-1 or PD-L1 inhibitor (including durvalumab).
  • A history of other primary malignancy except for:
  • Malignancy treated with curative intent and with no know active disease ≥ 5 years before the first dose of study drug 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
  • Currently receiving any other investigational agents.
  • Concurrent enrollment in another clinical study, unless it is an observational (non-interventional) clinical study or during the follow-up period of an interventional study.
  • Prior randomization or treatment in a previous durvalumab and/or tremelimumab clinical study regardless of treatment arm assignment.
  • Any unresolved toxicity NCI CTCAE grade ≥ 2 from previous anticancer therapy with the exception of alopecia, vitiligo, and the laboratory values defined in the inclusion criteria.
  • Patients with grade ≥ 2 neuropathy will be evaluated on a case-by-case basis after consultation with the PI.
  • Patients with irreversible toxicity not reasonably expected to be exacerbated by treatment with durvalumab or tremelimumab may be included only after consultation with the PI.
  • Radiotherapy treatment to more than 30% of the bone marrow or with a wide field of radiation within 4 weeks of the first dose of study drug.
  • Major surgical procedure (as defined by the PI) within 28 days prior to the first dose of study drug. Note: local surgery of isolated lesions for palliative intent is acceptable.
  • History of allogenic organ transplantation.
  • History of leptomeningeal carcinomatosis.
  • Any known history of brain metastases. Patients with known brain metastases must be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events.
  • A history of allergic reactions attributed to compounds of similar chemical or biologic composition to durvalumab, tremelimumab, or other agents used in the study.
  • Known allergy, or history of serious adverse reaction to vaccines such as anaphylaxis, hives, or respiratory difficulty.
  • Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, interstitial lung disease, serious chronic gastrointestinal conditions associated with diarrhea, or psychiatric illness/social situations that would limit compliance with study requirements, substantially increase the risk of incurring AEs, or compromise the ability of the patient to give written informed consent.
  • 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 first dose of study drug. Note: patients, if enrolled, should not receive live vaccine whilst receiving study drug and up to 30 days after the last dose of study drug.
  • History of syncopal or vasovagal episode as determined by medical record and history in the 12 month period prior to randomization
  • Individuals in whom a skinfold measurement of the cutaneous and subcutaneous tissue for eligible injection sites (left and right medial deltoid region) exceeds 40 mm.
  • Individuals in whom the ability to observe possible local reactions at the eligible injection sites (deltoid region) is, in the opinion of the investigator, unacceptably obscured due to a physical condition or permanent body art.
  • Therapeutic or traumatic metal implant in the skin or muscle of either deltoid region.
  • Any chronic or active neurologic disorder, including seizures and epilepsy, excluding a single febrile seizure as a child.
  • Current use of any electronic stimulation device, such as cardiac demand pacemakers, automatic implantable cardiac defibrillator, nerve stimulators, or deep brain stimulators.
  • Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease [e.g. colitis or Crohn's disease], diverticulitis [with the exception of diverticulosis], systemic lups erythematosus, Sarcoidosis syndrome 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 but only after consultation with the study physician
  • Patients with celiac disease controlled by diet alone
  • Pregnant and/or breastfeeding. Women of childbearing potential must have a negative pregnancy test within 14 days of study entry.
  • History of primary active immunodeficiency.
  • Active infection including tuberculosis (clinical evaluation that includes clinical history, physical examination and radiographic findings, and TB testing in line with local practice), hepatitis B (known positive HBV surface antigen (HBsAg) result), hepatitis C, or human immunodeficiency virus (positive HIV 1/2 antibodies). Patients with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody [anti-HBc] and absence of HBsAg) are eligible. Patients positive for hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA.

Gender Eligibility: All

Minimum Age: 18 Years

Maximum Age: N/A

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • Washington University School of Medicine
  • Collaborator
    • AstraZeneca
  • Provider of Information About this Clinical Study
    • Sponsor
  • Overall Official(s)
    • Jeffrey Ward, M.D., Ph.D., Principal Investigator, Washington University School of Medicine
  • Overall Contact(s)
    • Jeffrey Ward, M.D., Ph.D., 314-996-3362, jward2@wustl.edu

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