Patient case: 71-year-old female with lung cancer; genetic feature: ROS1

Clinical trial: A Trial of CV301 in Combination With Nivolumab Versus Nivolumab in Subjects With Previously Treated Non-Small Cell Lung Cancer

Summary: The objective of the proposed clinical study is to investigate the safety and tolerability of CV301 in combination with OPDIVO® (nivolumab), an anti PD1- inhibitor, compared to nivolumab alone in subjects with previously treated non-small cell lung cancer (NSCLC). The clinical study is designed to evaluate the possible enhanced antitumor activity of CV301 with nivolumab compared to nivolumab alone in a setting in which nivolumab is the standard-of-care, second-line therapy, for metastatic NSCLC. The rationale for combining CV301 with nivolumab is based on the hypothesis that CV301 can induce specific immune response in the tumor, and that in combination, nivolumab may augment the T cell-mediated immune response generated by CV301 by blocking the inhibitory signal of the PD-1.
  The study will include a Phase 1 dose escalation part to assess the safety and tolerability of CV301 alone, prior to moving into the combination with nivolumab (the Phase 1b component). The Phase 1 part of the trial will be followed by a Phase 1b component to test in a single arm lead-in stage the safety and tolerability of the combination treatment, i.e. CV301 plus nivolumab, before expanding the number of patients to be treated in the randomized Phase 2 part of the trial. The objective of the Phase 2 is to assess the safety and preliminary efficacy of CV301 in combination with nivolumab compared to nivolumab alone in subjects with previously treated NSCLC.


Eligibility: Inclusion criteria for the Phase 1:
  1. Patients must have a metastatic or unresectable locally advanced malignant solid tumor, histologically confirmed by the Laboratory of Pathology, NCI.
  2. Patients may have measurable or nonmeasurable but evaluable disease. Patients with surgically resected metastatic disease at high risk of relapse are also eligible.
  3. Prior therapy: Patients must have completed or had disease progression on at least one prior line of disease-appropriate therapy for metastatic disease, or not be candidates for therapy of proven efficacy for their disease.
  4. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving nivolumab.
  5. Men or women, age ≥ 18 years.
  6. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1 or Karnofsky ≥ 70%
  7. Patients must have normal organ and marrow function
  8. Patients must have baseline pulse oximetry > 90% on room air
  9. Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to trial entry and for the duration of trial participation and for a period of 4 months after the last vaccination therapy.
  10. Patients with prostate cancer must continue to receive GnRH agonist therapy (unless orchiectomy has been done).
  11. Patients must be able to understand and be willing to sign a written informed consent document
  Inclusion criteria for the Phase 1b and Randomized Phase 2:
  1. Histologically confirmed NSCLC, metastatic or unresectable locally advanced .
  2. EGFR mutation, ALK and ROS1 gene rearrangements will be allowed after progression on Standard of Care agent.
  3. Progression on or after prior platinum-based chemotherapy; switch maintenance therapy is considered part of the first-line regimen.
  4. ECOG performance status 0 and 1.
  5. Men or women, age ≥ 18 years
  6. Have normal organ and marrow function
  7. Have measurable disease by computed tomography (CT)/Magnetic resonance imaging (MRI) per RECIST 1.1.
  8. Willingness and ability to comply with scheduled visits, treatment plan, laboratory tests, and other trial procedures.
  9. Able to understand and be willing to sign a written informed consent document.
  10. Women of childbearing potential (WOCBP) must use appropriate method(s) of contraception. WOCBP should use an adequate method to avoid pregnancy for 23 weeks (30 days plus the time required for nivolumab to undergo five half-lives) after the last dose of investigational drug
  11. Women of childbearing potential must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) at screening and within 24 hours prior to the start of nivolumab
  Exclusion Criteria:
  1. Other concurrent investigational agents (subjects are eligible to enroll 4 weeks after completion of prior investigational agent).
  2. More than 1 prior chemotherapy regimen for locally advanced or metastatic NSCLC.
  3. Concurrent chemotherapy or radiotherapy or other immunotherapy.
  4. Prior therapy with an inhibitor of PD-1 or PD-L1 or PD-L2, or other experimental immunotherapeutic agents.
  5. Other malignancy within last 5 years, except non-melanoma skin cancer, in situ cervical, and controlled superficial bladder cancer.
  6. Active brain metastases or leptomeningeal metastases. Subjects with brain metastases are eligible if metastases have been treated and there is no magnetic resonance imaging (MRI) evidence of progression for 4 weeks after treatment is complete
  7. History of allergy or untoward reaction to prior vaccination with vaccinia virus, amynoglicoside antibiotics or egg products; history of allergy to smallpox vaccination.
  8. Active infection within 72 hours of vaccination
  9. Subjects should have no known evidence of being immunocompromised as listed below:
  1. Human immunodeficiency virus (HIV) positivity, chronic hepatitis infection, including B and C
  2. Active, known or suspected autoimmune disease.
  3. Immunosuppressive therapy post-organ transplant
  10. Altered immune function, including, but not limited to: inflammatory bowel disease ; active infectious enteritis; eosinophilic enteritis; Lupus erythematosus; ankylosing spondylitis; scleroderma; Multiple sclerosis; immunodeficiency or history of immunodeficiency; or other eczematoid skin disorders; or those with acute, chronic or exfoliative skin conditions (e.g., burns, impetigo, varicella zoster, severe acne, or other open rashes or wounds).
  11. Concurrent use of systemic steroids, except for physiologic doses of systemic steroids for replacement or local (topical, nasal, or inhaled) steroid use. Steroid eye-drops are contraindicated.
  Systemic steroids must have been discontinued ≥ 6 weeks prior to randomization.
  12. Subjects with interstitial lung disease that is symptomatic or may interfere with the detection or management of suspected drug-related pulmonary toxicity.
  13. Pregnant or breastfeeding women.
  14. Clinically significant cardiomyopathy, coronary disease, heart failure New York Heart Association class III or IV, cerebrovascular accident within 1 year.
  15. Uncontrolled intercurrent illness, which would interfere with the ability of the subject to carry out the treatment program.
  16. Any other condition, which would, in the opinion of the Principal Investigator or Medical Monitor, indicate the subject is a poor candidate for treatment with CV301 or would jeopardize the subject or the integrity of the data obtained.
  17. Medical or psychological impediment to compliance with protocol.

Relevance to patient case: not relevant