A phase II, multicenter, single-arm study of oral LDK378 in adult patients with ALK-activated non-small cell lung cancer previously treated with chemotherapy and crizotinib

Summary

This is a single-arm, open-label, multicenter, phase II study. Treatment with LDK378 750 mg qd will continue until the patient experiences unacceptable toxicity that precludes further treatment, discontinues treatment at the discretion of the investigator or patient, starts a new anticancer therapy and/or dies. LDK378 may be continued beyond RECISTdefined PD as assessed by the investigator if, in the judgment of the investigator, there is evidence of clinical benefit. In these patients tumor assessment should continue as per the schedule of assessments until treatment with LDK378 is permanently discontinued. Patients who discontinue the study medication in the absence of progression will continue to be followed for tumor assessment until the time of PD as assessed by the investigator.

This is a prospective, multi-center, open-label, single arm, non-randomized phase II study with a single stage design to evaluate the efficacy and safety of single-agent LDK378 in patients with ALK-rearranged NSCLC previously treated with cytotoxic chemotherapy (one to three prior lines) and then with crizotinib. Patients may also have received first line treatment with crizotinib followed by cytotoxic chemotherapy and, subsequently, a rechallenge treatment with crizotinib. All patients must have demonstrated progression on the last crizotinib treatment (i.e. crizotinib must be the last therapy prior to study entry) regardless of initial response. This population, as defined in the protocol eligibility criteria, has no available standard therapeutic options. The target population for this study is similar to the
ALK positive NSCLC population included in the ongoing phase I study of LDK378, as described above, where substantial anti-tumor activity of LDK378 has been demonstrated.

The primary objective is to demonstrate the antitumor activity of LDK378 in this population. The primary measure of antitumor activity is the overall response rate (ORR) according to Response Evaluation Criteria In Solid Tumors (RECIST) v1.1 and will be estimated based on investigator assessment. In addition, there will be an independent radiological review by a blinded independent review committee (BIRC). Response rate is an appropriate primary endpoint that can be adequately assessed in the context of this single arm phase II trial. A high ORR may predict clinical benefit in this rare population of patients with ALK-rearranged NSCLC that has progressed during crizotinib therapy and for whom there is no available alternate ALK-targeted therapy. Indeed, crizotinib was approved by certain Health Authorities in this indication based on data from two single arm trials using ORR based on investigator assessment as primary endpoint. Data on ORR will be supplemented with data on duration of response (DOR) and time to response (TTR).

Based on the response rate and safety data reported in a similar patient population in the ongoing phase I study (see Section 2.1), no futility analysis is warranted in the present study. The study will also assess progression-free survival (PFS), overall survival (OS) and impact on Patient Reported Outcomes (PROs) with LDK378 treatment. These endpoints are considered to be important supportive endpoints to better assess the potential clinical benefit
of LDK378.

Participant Eligibility

Patients eligible for inclusion in this study have to meet all of the following criteria:
1. Histologically or cytologically confirmed diagnosis of stage IIIb or IV
NSCLC that carries an ALK rearrangement defined as 15% or more positive tumor cells
as assessed by the FDA-approved Vysis ALK break-apart FISH test (Abbott Molecular Inc) using Vysis breakapart
probes. If documentation of ALK rearrangement is not available, the test to confirm
ALK rearrangement must be performed (preferably using a new tumor biopsy obtained
prior to the first LDK378 dose or, if not available, in archival tumor obtained at or since
the time of diagnosis) prior to study entry according to the above criteria. The test will be
performed at a Novartis designated central laboratory.
2. Age 18 years or older at the time of informed consent.
3. Patients must have stage IIIb or IV NSCLC that has progressed during
therapy with crizotinib or within 30 days of the last dose, regardless of whether the patient
had previously shown tumor regression or not:

* Crizotinib must have been the last prior systemic antineoplastic therapy received by
the patient prior to trial entry (radiotherapy is not considered a systemic antineoplastic
therapy)

* If a patient had received a first treatment with crizotinib prior to cytotoxic
chemotherapy and then received a second regimen of crizotinib after cytotoxic
chemotherapy, the patient is allowed to enter the study, but the patient must have
progressed on the most recent regimen of crizotinib (or within 30 days of last dose)

* Patients must have received their last dose of crizotinib >= 1 week prior to
the first dose of LDK378 and recovered from crizotinib toxicities (as defined in
inclusion criteria 5)
4. Patients must have received cytotoxic chemotherapy to treat their stage IIIb or IV NSCLC:

* All patients must have received at least one and a maximum of three prior lines of
cytotoxic chemotherapy

* Prior cytotoxic chemotherapy must include a platinum doublet

* Prior erlotinib or gefitinib will not count as a line of cytotoxic chemotherapy (i.e.
patients may have received prior treatment with these drugs)

* (Neo-)adjuvant cytotoxic chemotherapy will count as one prior line of treatment if
relapse occurred within 12 months from the end of the adjuvant cytotoxic
chemotherapy

* Note: A cytotoxic chemotherapy line in locally advanced or metastatic (stage IIIb or
IV) disease is defined as an anticancer regimen that contains at least 1 cytotoxic chemotherapy
agent and is given for 21 days or more. If a cytotoxic chemotherapy regimen was
discontinued for a reason other than disease progression and lasted less than 21 days,
then this regimen does not count as a prior line of chemotherapy
5. Patients must have archival tissue, collected either at the time of diagnosis of NSCLC or
any time since, available as a formalin-fixed, paraffin-embedded (FFPE) sample.
6. Patients must have recovered from all toxicities related to prior anticancer therapies to
grade <= 2 (CTCAE v 4.03). The exception to this criterion is for patients with grade 2
nausea/vomiting and/or grade 2 diarrhea despite optimal supportive therapy who will not
be allowed to participate in the study. Patients with any grade of alopecia are allowed to
enter the study.
7. Patients must meet the following laboratory values at the screening visit:

* Absolute neutrophil count (ANC) >= 1.5 x 109/L

* Platelets >= 75 x 109/L

* Hemoglobin (Hgb) > 8 g/dL

* Calculated creatinine clearance (using Cockcroft-Gault formula) > 30 mL/min

* Total bilirubin < 1.5 x ULN, (Upper limit of normal), except for patients with Gilbert[Single Quote]s syndrome, who may
only be included if total bilirubin < 3.0 x ULN or direct bilirubin < 1.5 x ULN

* Aspartate transaminase (AST) < 3 x ULN, except for patients with liver metastasis,
who are only included if ALT < 5 x ULN

* Alanine transaminase (ALT) < 3 x ULN, except for patients with liver metastasis,
who are only included if AST < 5 x ULN

* Patients must have the following laboratory values >= lower limit of normal (LLN) or
corrected to within normal limits with supplements during screening:

* Potassium >= LLN

* Magnesium >= LLN

* Phosphorus >= LLN

* Total calcium (corrected for serum albumin) >= LLN
8. Life expectancy >= 12 weeks.
9. World Health Organization (WHO) performance status 0-2.
10. 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
irradiation.
11. Written informed consent for the main study must be obtained prior to any screening
procedures. If consent cannot be expressed in writing, it must be formally documented and
witnessed, ideally via an independent trusted witness.
12. Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests
and other study procedures.