This research study is a Phase II clinical trial. Phase II clinical trials test the safety
and effectiveness of an investigational intervention to learn whether the intervention works
in treating a specific disease.
The FDA (the U.S. Food and Drug Administration) has approved Nivolumab as a treatment for
other types of cancers including lung cancer. However, the combination of Nivolumab with
other drugs (such as those being tested in this study) has not been approved by the FDA as a
treatment for this type of lung cancer.
The purpose of this study is to test the effectiveness (how well the drug works), safety, and
tolerability of the drug Nivolumab in combination with standard of care chemotherapies, or in
combination with Ipilimumab. Nivolumab and Ipilimumab are antibodies (a type of human
protein) that are being tested to see if they will allow the body's immune system to work
against tumor cells. This study is being done to see if Nivolumab and Ipilimumab, or
Nivolumab and chemotherapy drugs (Carboplatin and Pemetrexed), are more effective against
cancer when administered together.
These drugs are given as infusions. They are designed to "boost" the immune system's ability
to suppress or kill cancer cells that are foreign to the human body.
Inclusion Criteria:
- Histologically or cytologically confirmed advanced (stage IIIB or IV) non-small-cell
lung cancer (NSCLC).
- ALK-rearranged NSCLC: ALK rearrangement as assessed by ALK FISH, IHC, or
next-generation sequencing (NGS). For ALK FISH, rearrangements must be detected
in >15% of tumor cells.
- EGFR-mutant NSCLC: EGFR activating gene mutation (e.g., L858R, exon 19 deletion)
as well as a T790M mutation per local testing.
- Presence of at least one measurable lesion as defined by RECIST v1.1. A previously
irradiated site lesion may only be counted as a target lesion if there is clear sign
of progression since the completion of irradiation.
- Prior treatment with appropriate tyrosine kinase inhibitors (TKIs) as follows:
- ALK-positive NSCLC (cohorts B and D): Participants must have progressed on or
after 1 or more next-generation ALK-TKI(s).
- EGFR-mutant NSCLC (cohorts A and C): Participants must have progressed on or
after 1 or more third-generation, T790M mutant-selective EGFR-TKI(s).
- Prior systemic chemotherapy requirements are as follows:
- Nivolumab plus carboplatin and pemetrexed arms (cohorts A and B): NO prior
systemic chemotherapy is allowed. NOTE: Prior adjuvant or neoadjuvant
chemotherapy is allowed if received more than 12 months prior to the study.
- Nivolumab plus ipilimumab arms (cohorts C and D): Participants must have received
a platinum-based combination chemotherapy for their advanced lung cancer and
either progressed on/after this chemotherapy or are intolerant. Only ONE line of
chemotherapy is allowed. NOTE: Prior adjuvant or neoadjuvant chemotherapy does
not count as an additional line of chemotherapy if received more than 12 months
prior to the study.
- Tumor tissue sample is required following the participant's last line of systemic
therapy (TKI or chemotherapy). Tissue sample may be fresh (core needle, excisional, or
incisional biopsy), or archival if obtained within 6 months prior to enrollment. There
can have been no systemic therapy administered after the sample was obtained. If a
tissue sample is available but it has been > 6 months and there has been no
intervening therapy, the Principal Investigator may approve the sample after
discussion. PD-L1 IHC testing will be performed on the tumor tissue, but positivity on
the PD-L1 IHC testing is not required to enroll in the study.
- Clinically asymptomatic and stable central nervous system (CNS) metastases are allowed
(including untreated CNS metastases) if they have not required increasing doses of
steroids or stable doses equivalent to prednisone > 10 mg daily within 2 weeks prior
to study entry for CNS symptoms.
- Prior palliative radiotherapy must have been completed at least 2 weeks prior to study
entry.
- Subjects must have been off any prior systemic anti-cancer treatment (including TKIs)
for at least 5 half-lives of that drug.
- Age ≥ 18 years old.
- ECOG performance status of 0 or 1.
- Life expectancy ≥ 12 weeks.
- Screening laboratory values must meet the following criteria:
- WBC ≥ 2.0 x 109/L
- Neutrophils ≥ 1.5 x 109/L
- Platelet ≥ 100 x 109/L
- Hemoglobin ≥ 9/dL
- Serum creatinine ≤ 1.5 x ULN or calculated creatinine clearance using
Cockcroft-Gault formula ≥ 50 mL/min
- Female CrCl = (140-age in years) x weight in kg x 0.85 72 x serum creatinine
in mg/dL
- Male CrCl = (140 - age in years) x weight in kg x 1.00 72 x serum creatinine
in mg/dL
- Total bilirubin ≤ 1.5 x ULN (except in patients with Gilbert's syndrome who may
have total bilirubin < 3.0 mg/dL)
- AST and ALT ≤ 3.0 x ULN (or ≤ 5.0 x ULN if liver metastases are present)
- Females of child-bearing potential (defined as a sexually mature woman who has not
undergone a hysterectomy or bilateral oophorectomy or has not been naturally
post-menopausal for at least 24 consecutive months) must:
- Have a negative serum or urine pregnancy test obtained within 24 hours prior to
starting the investigational drug.
- Not be breastfeeding.
- Agree to use, and be able to comply with, highly effective contraception (failure
rate less than 1% per year) without interruption while on study treatment plus 5
half-lives of nivolumab (half-life up to 25 days) plus 30 days (duration of
ovulatory cycle) for a total of 23 weeks post treatment completion. Complete
abstinence is acceptable if it is in line with the preferred and usual lifestyle
of the patient. Period abstinence (e.g., calendar, ovulation, symptothermal, or
postovulation methods) and withdrawal are not acceptable methods of
contraception. Examples of non-hormonal contraceptive methods with a failure rate
of < 1% per year include bilateral tubal ligation, male sterilization, hormonal
implants, established and proper use of combined oral or injected hormonal
contraceptives, and certain intrauterine devices. Alternatively, two methods
(e.g., two barrier methods from the options of diaphragm, cervical cap, vaginal
sponge, and condom, or progesterone-only oral hormonal contraception where
inhibition of ovulation is not the primary mode of action) may be combined to
achieve a failure rate of < 1% per year. Barrier methods must always be
supplemented with the use of a spermicide.
- Male subjects agree to remain abstinent or use a condom plus an additional
contraceptive method that result in a failure rate of <1% per year during sexual
contact with a female of childbearing potential while participating in the study,
during dose interruptions, and for 31 weeks following the last dose of the study
treatment, even if he has undergone a successful vasectomy. Abstinence is only
acceptable if it is in line with the preferred and usual lifestyle of the patient.
Periodic abstinence and withdrawal are not acceptable.
- Subject has the ability to understand and provide signed informed consent.
- Subject has the willingness and ability to comply with scheduled visits, treatment
plans, laboratory tests, and other study procedures
Exclusion Criteria:
- Subjects previously treated with T cell immune-modulating antibodies, including
anti-CTLA-4, anti-PD-1 and/or anti-PD-L1 agents.
- Subjects with symptomatic brain metastases, carcinomatous meningitis, spinal cord
compression, or intractable back pain due to compression of destructive mass.
- Subjects with active, known, or suspected autoimmune disease. Subjects with type I
diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders
(such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, or
conditions not expected to recur in the absence of an external trigger are permitted
to enroll.
- Subjects with a condition requiring systemic treatment with either corticosteroids (>
10 mg daily prednisone equivalent) or other immunosuppressive medications within 14
days of randomization (unless used to treat investigational drug-related adverse
events). Inhaled or topical steroids, and adrenal replacement steroid doses > 10 mg
daily prednisone equivalent, are permitted in the absence of active autoimmune
disease.
- Subjects with interstitial lung disease or interstitial pneumonitis that is
symptomatic or may interfere with the detection or management of suspected
drug-related pulmonary toxicity.
- Subjects must have recovered from the effects of major surgery or significant
traumatic injury at least 14 days prior to screening. No major surgery, other than
diagnostic surgery, is allowed within 4 weeks prior to treatment in the study.
- Co-administration of anti-cancer therapies other than those administered in the study.
- Subjects with other active malignancy requiring concurrent intervention.
- Known history of testing positive for human immunodeficiency virus (HIV) or known
acquired immunodeficiency syndrome (AIDS). HIV-positive participants are ineligible
because these participants are at increased risk of lethal infections when treated
with marrow-suppressive therapy, and because there is the potential for
pharmacokinetic interactions with combination antiretroviral therapy and study drugs.
- Any positive test for hepatitis B virus or hepatitis C virus indicating acute or
chronic infection.
- Subjects with ≥ grade 2 peripheral neuropathy at enrollment per the National Cancer
Institute Common Terminology Criteria for Adverse Events (NCI CTCAE).
- Pregnant or lactating women. Pregnant women are excluded from this study because the
study drugs (i.e., nivolumab, ipilimumab, carboplatin, and pemetrexed) have the
potential for teratogenic or abortifacient effects. Because there is an unknown but
potential risk for adverse events in nursing infants secondary to treatment of the
mother with these agents, breastfeeding should be discontinued.
- Subjects currently enrolled in any other clinical protocol or investigational trial
that involves administration of experimental therapy and/or therapeutic devices, or
investigational drug.
- History of allergy or hypersensitivity to any study drugs or their excipients.
- Any known clinically significant concomitant medical condition, laboratory
abnormality, or psychiatric illness that, in the investigator's opinion, would prevent
the subject from participating in the study, pose an unacceptable risk to the patient
in this study, or interfere with the interpretation of safety results.
