Phase 2 open label trial of oral intermittent dacomitinib in patients with advanced NSCLC
- Zale Lipshy University Hospital
This is a multi-center, Phase 2 open-label trial of intermittent dacomitinib in two
cohorts of patients with advanced nSCLC. These cohorts will enroll concurrently:
* Cohort a will include patients whose tumor has a documented T790M mutation
in exon 20 of the epidermal Growth Factor Receptor (eGFR). This Cohort will
enroll at least 15 patients.
* Cohort B will not require a specific molecular signature, but excludes patients
with known T790M mutations.
* The primary endpoint is Best overall Response (BoR) per Response evaluation
Criteria in Solid Tumors (ReCiST) v1.1, in Cohort a.
* a key secondary endpoint is to characterize the effects of dacomitinib and its
major circulating metabolite, PF-05199265, on QTc. overall, approximately
35 patients will be enrolled, across Cohorts a and B combined, to ensure
adequate numbers of patients are evaluable for the QTc assessments.
Cohorts a and B
Lead-in/Cycle 0 (1 week cycle):
* Day 1, Serial baseline (pre-dose) eCG recordings will be collected as outlined in the
Schedule of activities, prior to first dose of study drug in the evening.
* Day 1: 45 mg in the evening (first dose).
* Days 2 and 3: 45 mg Q 12 hour.
* Day 4: During a morning clinical site visit, a 45 mg dose will be administered to
patients and serial PK samples and time-matched eCG recordings will be collected as
outlined in the Schedule of activities (Soa). Dosing for this cycle will be complete
and there will be no evening dose.
* Days 5-7: no Dosing.
Following the Lead-in cycle, if patients have no ongoing treatment-related aes [GreaterThanorequalTo] Grade 3,
and no intolerable Grade 2 events, dose escalation to 60 mg will occur in Cycle 1.
Cycle 1 (two-week cycle):
* Day 1 Pre-dose PK sample and eCG recordings will be collected according to the
Soa and 60 mg dose will be administered starting in the evening after clinical site
* Days 2 and 3: 60 mg Q 12 hour.
* Day 4: During a clinical site visit, pre-dose PK sample and pre-dose eCG recordings
will be collected according to Soa and a 60 mg dose will be administered to patients.
* Days 5-14: no dosing.
* Day 8: Clinic visit to assess aes and tolerance.
Cycles 2 and Beyond
after consultation with, and agreement confirmed in writing by Sponsor, intra-patient dose
escalation beyond 60 mg will be considered if a patient has demonstrated tolerance of their
current dose for at least two cycles and the patient has no treatment related ae [GreaterThanorequalTo] Grade 3 or
intolerable treatment related Grade 2 aes ongoing. Doses will be increased by 15 mg for
each dose within a cycle (eg, 60 mg Q12h x 6 doses will increase to 75 mg Q12h x 6 doses).
no intra-cycle dose escalation is allowed.
Cycles with Dose escalation
in all cycles where the patient has had a dose escalation to a new, higher dose, the patient
must be seen in clinic on the same schedule and for the same assessments as in Cycle 1. See
Soa for details.
* Cycles without Dose escalation
Cycles without dose escalation will not require clinic visits after Day 1. Patients will take
their dacomitinib on the same dosing schedule as above (6 doses/cycle, Q12 h).
no dose escalation above the 60mg dose used in Cycle 1 will be allowed in Cohort B.
asessments and clinical visits will be as outlined in the Soa.
Patient eligibility should be reviewed and documented by an appropriately qualified member
of the Investigator[Single Quote]s study team before patients are included in the study.
Patients must meet all of the following inclusion criteria to be eligible for enrollment into the
1. Evidence of a personally signed and dated informed consent document indicating that
the patient (or a legal representative) has been informed of all pertinent aspects of the
2. Willingness and ability to comply with scheduled visits, treatment plan, laboratory
tests, and other study procedures.
3. Age >=18 years, male or female.
4. Evidence of histologically confirmed, advanced NSCLC (stage IIIB/IV).
a. Cohort A: Patients whose tumor has a T790M mutation in exon 20 of EGFR.
T790M mutation assay can be performed at investigational sites using a Sponsor
approved assay methodology.
b. Cohort B: Patients with advanced NSCLC for whom a panHER therapy would be
appropriate. Molecular characteristics of tumor not required; if known, then the
tumor must not have a T790M mutation for the patient to be enrolled in Cohort B
(patients with T790M mutations may only enroll in Cohort A).
5. Prior Therapy:
a. Cohort A: Patients who have received any number of prior chemotherapy
regimens, including zero, are eligible. Patients may have had a prior approved reversible
EGFR directed therapy, but not experimental or irreversible EGFR-directed therapy. If patients
have had prior reversible EGFR-directed therapy:
- Patients must have progressed on an approved reversible EGFR-directed therapy,
- The reversible EGFR-directed therapy needs to have been given as a single agent (ie,
cannot have been given concurrently with any other anti-cancer agents).
- Patients must not have had any systemic therapy (chemotherapy or
investigational agent) between the time of progression on reversible EGFR-directed
therapy and study enrollment, Continuation of the patient[Single Quote]s prior reversible EGFR-directed therapy is allowed until the time outlined in Inclusion Criterion #7.
- The gap between discontinuation of reversible EGFR- directed therapy and beginning the
study must be no greater than 6 weeks.
b. Cohort B: 0-1 prior lines of systemic cytotoxic therapy. Patient may have also
received prior reversible EGFR-directed therapy (but not irreversible EGFR directed therapy) .
6. ECOG 0-2 performance status.
7. Any prior cytotoxic chemotherapy, radiation therapy (other
than palliative radiotherapy to lesions that will not be followed for tumor assessment
on this study, ie, non-target lesions), or surgery (not including minor procedures such
as lymph node biopsy) must have been completed at least 2 weeks prior to
enrollment. Prior Tarceva or Iressa treatment may continue until 3 days prior to start
of dosing if, in the judgment of the investigator, there is risk that a patient with an
EGFR mutation could experience rapid progression (
* disease flare
* ) upon withdrawal
of EGFR TKI therapy. Any other prior reversible EGFR-directed treatment must
have been completed at least 5x the length of that drug[Single Quote]s terminal half life prior to
start of dosing. Any acute toxicity must have recovered to <= Grade 1 (per NCI
CTCAE v4) or baseline.
8. Measurable disease by RECIST criteria:
a. At least one target lesion, that has not previously been radiated, measurable in at
least one dimension of greater than 1 cm by CT or MRI;
- Acceptable radiologic procedures for disease assessment include contrast
enhanced CT or MRI; non -contrast enhanced CT scans are only allowed in
the instance of known contrast-allergy and patient intolerance of MRI. The
following are not allowed as sole documentation of target lesions: ultrasound
alone, nuclear scans (including bone or PET scans), plain CXR or bone
radiographs, and tumor markers.
b. Palpable disease which is biopsy proven to be metastatic NSCLC (eg, skin nodule
or lymphadenopathy), superficial, and measurable by caliper is allowed, though
confirmation of measurement by CT or ultrasound is encouraged;
9. Adequate Renal Function, including:
a. Estimated creatinine clearance >=30 mL/min (as determined by site[Single Quote]s standard
b. No known history of renal papillary necrosis or chronic pyelonephritis.
10. Adequate Liver Function, including:
a. Bilirubin <=1.5 x upper limit of normal (ULN);
b. AST (SGOT) <=2.5 x ULN (<=5.0 x ULN if hepatic metastases);
c. ALT (SGPT) <=2.5 x ULN (<=5.0 x ULN if hepatic metastases).
11. Urine/serum pregnancy test (for females of childbearing potential) negative on two
occasions prior to starting study therapy - at screening and at the baseline visit (within
72 hours prior to Cycle 0 Day 1). (See Section 7.2 Pregnancy Testing).
12. Male and female patients of childbearing potential must agree to use two (2) highly
effective methods of contraception throughout the study and for at least 90 days after
the last dose of study treatment (See Section 4.3 Life Style Guidelines). A patient is
of childbearing potential if, in the opinion of the Investigator, he/she is biologically
capable of having children and is sexually active.