Business decision

This is a Phase I open label multi-center study to evaluate the safety, tolerability, pharmacokinetics and preliminary effectiveness of the investigational drug MYTX-011 in patients with locally advanced, recurrent or metastatic NSCLC. MYTX-011 is in a class of medications called antibody drug conjugates (ADCs). MYTX-011 is composed of a pH-dependent anti-cMET antibody and the potent antimicrotubule drug monomethyl auristatin E (MMAE).

The study will be conducted in 2 parts. Part 1 will assess the safety and tolerability of MYTX-011 and identify the dose to be studied in Part 2. Part 2 will include subjects with NSCLC with cMET overexpression or MET amplification/exon 14 skipping mutations, populations with a current unmet medical need.

Inclusion Criteria:

Part 1:

• Histologically or cytologically confirmed locally advanced, recurrent or metastatic NSCLC and have received available standard of care therapy.
• There is no limit on the number of prior therapies that can have been received.

Part 2 Cohorts A-D and F

1. Known to not have an actionable EGFR mutation. Subjects with or without other driver mutations are permitted to enroll.
2. Must have received (or be ineligible for) available standard of care therapy.
3. Must have progressed on at least 1 line of prior systemic therapy in the locally advanced/metastatic setting. Note: multiple TKIs for the same actionable mutation count as 1 line of therapy. Rechallenge of the same therapy regimen within 6 months of discontinuation date of the therapy is not considered a separate line of therapy. Maintenance therapy is not considered a separate line of therapy. Adjuvant and neoadjuvant therapies count as 1 line of therapy if given within 6 months before study entry. The same rules above apply to all inclusion/exclusion criteria regarding prior lines of therapy.
4. Subjects without any actionable gene alteration: must have progressed on (or be considered ineligible for), or be intolerant to, platinum-based chemotherapy and immune checkpoint inhibitor (as monotherapy or in combination with chemotherapy) and have not received more than 2 lines of prior systemic therapy in the locally advanced/metastatic setting.
5. Subjects with actionable gene alterations (other than EGFR) for which immune checkpoint inhibitor therapy is not standard of care (e.g., anaplastic lymphoma kinase [ALK] translocation): must have progressed on (or be considered ineligible for), or be intolerant to, anticancer therapy targeting driver gene alterations and platinum-based chemotherapy and have not received more than 3 lines of prior systemic therapy in the locally advanced/metastatic setting.
6. Subjects with actionable gene alterations (other than MET exon 14 skipping mutation) for which immune checkpoint inhibitor is standard of care: must have progressed on (or be considered ineligible for), or be intolerant to, anticancer therapy targeting driver gene alteration and platinum-based chemotherapy, and also progressed on (or be considered ineligible for) or be intolerant to immune checkpoint inhibitor(as monotherapy or in combination with platinum-based chemotherapy, and have not received more than 3 lines of prior systemic therapy in the locally advanced/metastatic setting.
7. Subjects with MET exon 14 skipping mutation must have progressed on, or be intolerant to, at least one MET TKI if available, and have not received more than 2 lines of prior systemic therapy in the locally advanced/metastatic setting.

Part 2:

Cohort A:

• Have histologically or cytologically confirmed locally advanced, recurrent (and not a candidate for curative therapy), or metastatic non-squamous NSCLC without EGFR mutation.
• Tumor sample with high cMET expression by IHC confirmed by central laboratory testing.

Cohort B:

• Have histologically or cytologically confirmed locally advanced, recurrent (and not a candidate for curative therapy), or metastatic non-squamous NSCLC without EGFR mutation.
• Tumor sample with intermediate cMET expression by IHC confirmed by central laboratory testing.

Cohort B2

• Have histologically or cytologically confirmed locally advanced, recurrent (and not a candidate for curative therapy), or metastatic non-squamous NSCLC without EGFR mutation.
• Tumor sample with intermediate cMET expression by IHC confirmed by central laboratory testing.

Cohort C:

• Have histologically or cytologically confirmed locally advanced, recurrent (and not a candidate for curative therapy), or metastatic squamous NSCLC without EGFR mutation.
• Tumor sample with cMET expression by IHC confirmed by central laboratory testing.

Cohort D:

• Have histologically or cytologically confirmed locally advanced, recurrent (and not a candidate for curative therapy), or metastatic non-squamous or adenosquamous NSCLC without EGFR mutation.
• Tumor sample with low cMET expression on tumor biopsy confirmed centrally by IHC that does not meet inclusion criteria for Cohorts A, B, or B2.

Cohort E:

• Have histologically or cytologically confirmed locally advanced, recurrent (and not a candidate for a curative therapy), or metastatic NSCLC with actionable EGFR mutations.
• Tumor sample with high or intermediate cMET expression by IHC confirmed by central laboratory testing.
• Must have received an available standard of care therapy and have progressed on at least 1 and no more than 3 lines of prior systemic therapy in the locally advanced/metastatic setting.

Cohort E2

• Have histologically or cytologically confirmed locally advanced, recurrent (and not a candidate for curative therapy), or metastatic NSCLC with actionable EGFR mutations.
• Tumor sample with high or intermediate cMET expression by IHC confirmed by central laboratory testing.
• Must have received an available standard of care therapy and have progressed on at least 1 line and no more than 3 lines of prior systemic therapy in the locally advanced/metastatic setting.

Cohort F

• Have histologically or cytologically confirmed locally advanced non-squamous or adenosquamous NSCLC without EGFR mutation.
• Have ultra-low cMET expression on tumor biopsy confirmed centrally by IHC that does not meet inclusion criteria for Cohorts A,B, B2, or D.

All patients (Part 1 and Part 2)

Inclusion Criteria:

• Patient has at least one measurable lesion per RECIST 1.1
• ECOG performance status 0 or 1
• For women of childbearing potential and men with partners of childbearing potential, agreement to use a highly effective method of birth control for the duration of the study treatment and for at least 6 months after the last dose of study drug.
• Able to provide informed consent, and willing and able to comply with study protocol requirements

Exclusion Criteria:

Radiation to the lung within 6 weeks prior to screening. For all other sites (except lung), therapeutic or palliative radiation within 2 weeks prior to the first dose of study drug. Must have recovered from all radiation-related toxicity.

Major surgery within 28 days of first dose of study drug administration.

Untreated, uncontrolled central nervous system (CNS) metastases and/or leptomeningeal disease.

• History of interstitial lung disease or pneumonitis that required treatment with systemic steroids or evidence of active interstitial lung disease or pneumonitis. A history of prior radiation pneumonitis in the radiation field (fibrosis) is permitted.
• Clinically significant systemic illness that could pose undue risk to the subject or confound the ability to interpret study results.
• Active infection requiring IV antibiotics, antivirals, or antifungal medication within 14 Days of Cycle 1 Day 1
• Neuropathy > Grade 1
• History of cirrhosis, hepatic fibrosis, esophageal or gastric varices, or other clinically significant liver disease.
• Active or chronic corneal disorder
• Conditions that may interfere with assessment of vision, such as monocular status or severe visual impairment in 1 or both eyes

At the conclusion of the study