The researchers think that the study drugs, amivantamab and lazertinib, may be an effective treatment for people who have metastatic NSCLC with an EGFR mutation. Both drugs work to target cancer cells with an EGFR mutation, and this targeting action could stop or slow the growth of cancer cells. The researchers are doing this study to find out how well amivantamab and lazertinib work against metastatic NSCLC with an EGFR mutation.
Not yet recruiting
Phase 2
| Drug | Synonyms | Arms |
|---|---|---|
| Amivantamab | Patients with leptomeningeal (LM) disease with or without parenchymal brain metastases | |
| Lazertinib | Patients with leptomeningeal (LM) disease with or without parenchymal brain metastases |
| Name | Type | Description | Interventions |
|---|---|---|---|
| Patients with parenchymal brain metastases | Experimental | All patients in both cohorts will receive both oral lazertinib and amivantamab by intravenous injection (IV). Lazertinib dosing will start at 240 mg daily. For patients who weigh <80 kg, on C1D1 amivantamab 350 mg will be given IV via peripheral line for C1D1, D2 and D8, with 700 mg IV given on C1D2. For all other treatments, amivantamab 1050 mg IV will be given. For patients who weigh ≥ 80 kg, on C1D1 350mg IV amivantamab will be given and 1050 mg IV on C1D2, with 1400 mg IV given for all. |
|
| Patients with leptomeningeal (LM) disease with or without parenchymal brain metastases | Experimental | All patients in both cohorts will receive both oral lazertinib and amivantamab by intravenous injection (IV). Lazertinib dosing will start at 240 mg daily. For patients who weigh <80 kg, on C1D1 amivantamab 350 mg will be given IV via peripheral line for C1D1, D2 and D8, with 700 mg IV given on C1D2. For all other treatments, amivantamab 1050 mg IV will be given. For patients who weigh ≥ 80 kg, on C1D1 350mg IV amivantamab will be given and 1050 mg IV on C1D2, with 1400 mg IV given for all. |
|
Inclusion Criteria:
- Age ≥18 years
- Written informed consent
- Advanced biopsy-proven metastatic or recurrent non-small cell lung cancer
- Somatic activating mutation in EGFR in a prior tumor biopsy or cfDNA sample
- Patients will have progressed on standard of care therapies
- Patients with EGFR exon 20 insertions will have progressed on platinum-based
chemotherapy
- Patients with EGFR alterations sensitizing to tyrosine kinase inhibitors (TKIs)
will have progressed on osimertinib
- Patients will be allowed to have received other systemic therapies since
progression on the above, including investigational agents at least 28 days or 5
half lives prior to the first dose of study drug, whichever is shorter
- For Cohort A, subjects must have at least one measurable (at least 10 mm) intracranial
disease according to RECIST 1.1.
- For Cohort A, subjects must have new or progressing CNS metastases. Extracranial
measurable disease is not required.
- For Cohort B, subjects must have evidence of LM involvement by positive CSF cytology
or presence of CTCs in CSF. Extracranial measurable disease is not required.
- Recent extracranial tissue biopsy within 8 weeks of C1D1 or willingness to undergo a
repeat tumor biopsy. If subjects do not have an extracranial lesion amenable to
biopsy, this requirement may be waived.
- Karnofsky performance status (KPS) ≥60%
- Ability to swallow oral medications
- Adequate organ function
- Hemoglobin ≥ 9 g/dL
- Platelets ≥ 75 x 10^9/L
- Absolute neutrophil count (ANC) >1.5 x 10^9/L
- AST, ALT ≤ 3 x ULN (if liver metastases are present, ≤5 × ULN)
- Total bilirubin ≤1.5 x ULN if no liver metastases or <3 × ULN in the presence of
documented Gilbert's Syndrome (unconjugated hyperbilirubinemia) or liver
metastases; subjects with Gilbert's syndrome can enroll if conjugated bilirubin
is within normal limits
- Serum creatinine <1.5 x ULN or if available, calculated using the Cockcroft-Gault
equation or measure creatine clearance >50mL/min/1.73 m^2
- Before enrollment, a women must be either:
- Not of childbearing potential: premenarchal; postmenopausal (>45 years of age
with amenorrhea for at least 12 months); permanently sterilized (e.g., bilateral
tubal occlusion [which includes tubal ligation procedures as consistent with
local regulations], hysterectomy, bilateral salpingectomy, bilateral
oophorectomy); or otherwise be incapable of pregnancy
- Of childbearing potential and practicing effective method(s) of birth control
consistent with local regulations regarding the use of birth control methods for
subjects participating in clinical studies, as described below:
- Practicing true abstinence (when this is in line with the preferred and usual
lifestyle of the subject), which is defined as refraining from heterosexual
intercourse during the entire period of the study, including up to 6 months after
the last dose of study drug is given. Periodic
- abstinence (calendar, symptothermal, post-ovulation methods) is not consider an
acceptable contraceptive method
- Have a sole partner who is vasectomized
- Practicing 2 methods of contraception, including one highly effective method
(i.e., established use of oral, injected or implanted hormonal methods of
contraception; placement of intrauterine device [IUD] or intrauterine system
[IUS], AND, a second method (e.g., condom with spermicidal
foam/gel/film/cream/suppository or collusive cap [diaphragm or cervical/vault
caps] with spermicidal foam/gel/film/ cream/suppository)
- Subjects must agree to continue contraception throughout the study and continuing
through 6 months after the last dose of study drug
- NOTE: If the childbearing potential changes after start of the study (e.g., woman
who is not heterosexually active becomes active, premenarchal woman experiences
menarche) the woman must begin a highly effective method of birth control, as
described above.
- A woman of childbearing potential must have a negative serum (b-human chorionic
gonadotropin [b-hCG]) at Screening
- A woman must agree not to donate eggs (ova, oocytes) for the purposes of assisted
reproduction during the study and for 6 months after receiving the last dose of study
drug
- A man who is sexually active with a woman of childbearing potential must agree to use
a condom with spermicidal foam/gel/film/cream/suppository and his partner must also be
practicing a highly effective method of contraception (i.e., established use of oral,
injected or implanted hormonal methods of contraception; placement of an intrauterine
device [IUD] or intrauterine system [IUS]). If the subject is vasectomized, he must
still use a condom (with or without spermicide), but his female partner is not
required to use contraception. The subject must also not donate sperm during the study
and for 6 months after receiving the last dose of study drug
Exclusion Criteria:
- Pregnant or lactating women
- Any radiotherapy within 1 week of starting treatment on protocol
- Any major surgery within 1 week of starting treatment on protocol
- Clinically significant toxicities from previous treatment
- Previous systemic chemotherapy within 2 weeks of starting treatment on protocol
- EGFR TKI or other oral treatment within 3 days of starting treatment on protocol
- Interstitial lung disease (ILD), including drug-induced ILD or radiation pneumonitis
requiring prolonged steroids or other immune suppressive agents that is unresolved or
resolved within the last 3 months
- Progressive neurological symptoms requiring escalating doses of steroids or not
controlled with steroids
- Positive hepatitis B (hepatitis B virus [HBV]) surface antigen (HBsAg)
- NOTE: Subjects with a prior history of HBV demonstrated by positive hepatitis B core
antibody are eligible if they have at Screening 1) a negative HBsAg and 2) a HBV DNA
(viral load) below the lower limit of quantification, per local testing. Patients who
fit these criteria must use Hep B prophylaxis during treatment. Subjects with a
positive HBsAg due to recent vaccination are eligible if HBV DNA (viral load) is below
the lower limit of quantification, per local testing
- Positive hepatitis C antibody (anti-HCV)
- NOTE: Subjects with a prior history of HCV, who have completed antiviral treatment and
have subsequently documented HCV RNA below the lower limit of quantification per local
testing are eligible
- Other clinically active or chronic liver disease
- Subject has uncontrolled inter-current illness, including but not limited to poorly
controlled hypertension or diabetes, ongoing or active infection (i.e., has
discontinued all antibiotics for at least one week prior to first dose of study drug),
or psychiatric illness/social situation that would limit compliance with study
requirements. Subjects with medical conditions requiring chronic continuous oxygen
therapy are excluded.
- Pulmonary embolism (PE) and deep vein thrombosis (DVT), within 1 month of start of
study drug
- Myocardial infarction, unstable angina, stroke, transient ischemic attach (TIA), or
coronary/peripheral artery bypass graft, or any acute coronary syndrome within 6
months of start of study drug
- Congestive heart failure defined as New York Heart Association (NYHA) Class III-IV or
hospitalization for congestive heart failure (any NYHA class) within 6 months of study
Day 1
- Prolonged QTcF interval >480 msec or clinically significant cardiac arrhythmia or
electrophysiologic disease (e.g., placement of implantable cardioverter defibrillator
or atrial fibrillation with uncontrolled rate). Note: Subjects with cardiac pacemakers
who are clinically stable are eligible
- Immune-mediated rash from checkpoint inhibitors that has not resolved prior to
enrollment
- Contraindication or inability to undergo serial MRIs
- Recent use of amiodarone, phenobaritone, and other prohibited medications
| Maximum Eligible Age: | N/A |
| Minimum Eligible Age: | 18 Years |
| Eligible Gender: | All |
| Healthy Volunteers: | No |
| Measure: | CNS overall response rate (ORR) (Cohort 1) |
| Time Frame: | 2 years |
| Safety Issue: | |
| Description: | Per Response Evaluation Criteria in Solid Tumors (RECIST v1.1) in patients with EGFR-mutant lung cancer with progressive or new parenchymal brain metastases. |
| Phase: | Phase 2 |
| Primary Purpose: | Interventional |
| Overall Status: | Not yet recruiting |
| Lead Sponsor: | Memorial Sloan Kettering Cancer Center |
August 3, 2021
