Testing Copanlisib as Potentially Targeting Treatment in Cancers With PTEN Loss (MATCH - Subprotocol Z1G)

MATCH Treatment Subprotocol Z1G: Phase II Study of Copanlisib in Patients With Tumors With PTEN Loss by IHC and Any PTEN Sequencing Result

The phase II MATCH treatment trial tests how well copanlisib works to treat patients with cancer with PTEN loss. Copanlisib may stop the growth of tumor cells and may kill them by blocking some of the enzymes needed for cell growth.

PRIMARY OBJECTIVE:

I. To evaluate the proportion of patients with objective response (OR) to targeted study agent(s) in patients with advanced refractory cancers/lymphomas/multiple myeloma.

SECONDARY OBJECTIVES:

I. To evaluate the proportion of patients alive and progression free at 6 months of treatment with targeted study agent in patients with advanced refractory cancers/lymphomas/multiple myeloma.

II. To evaluate time until death or disease progression. III. To identify potential predictive biomarkers beyond the genomic alteration by which treatment is assigned or resistance mechanisms using additional genomic, ribonucleic acid (RNA), protein and imaging-based assessment platforms.

IV. To assess whether radiomic phenotypes obtained from pre-treatment imaging and changes from pre- through post-therapy imaging can predict objective response and progression free survival and to evaluate the association between pre-treatment radiomic phenotypes and targeted gene mutation patterns of tumor biopsy specimens.

OUTLINE:

Patients receive copanlisib intravenously (IV) at a dose of 60 mg over 1 hour on day 18 and 15 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo tumor biopsy on study and radiologic evaluation and blood sample collection throughout the study.

After completion of study treatment, patients are followed up every 3 months for 2 years and then every 6 months for 1 year.

THE MATCH SCREENING TRIAL:

Please see NCT02465060 for information on the MATCH Screening Protocol and applicable documents.

Inclusion Criteria:

• Patients must have met applicable eligibility criteria in the Master MATCH Protocol EAY131/ NCI-2015-00054 prior to registration to treatment subprotocol

• Patients must fulfill all eligibility criteria outlined in Section 3.1 of MATCH Master Protocol (excluding Section 3.1.6) at the time of registration to treatment step (Step 1, 3, 5, 7)

• Patients must have complete loss of cytoplasmic and nuclear PTEN by immunohistochemistry (ICH) as determined via the MATCH Master Protocol and described in Appendix I. Patients can have any PTEN mutation or deletion status, but MUST have PTEN loss by IHC

  • NOTE: For patients entering the study, all patients must have PTEN IHC performed as described in the MATCH Master Protocol. This includes patients entering the study via the outside assay process

• Patients must not have co-existing aberrations in the MAPK or PI3K/MTOR pathways as determined by the MATCH screening assessment in NRAS, HRAS, KRAS, BRAF, PIK3CA, AKT or mTOR

• Patients must have an electrocardiogram (ECG) within 8 weeks prior to treatment assignment and must have no clinically important abnormalities in rhythm, conduction or morphology of resting ECG (e.g. complete left bundle branch block, third degree heart block)

• Patients must not have known hypersensitivity to copanlisib or compounds of similar chemical or biologic composition

• Patients must not have had prior treatment with copanlisib or other PI3K inhibitors, AKT inhibitors or mTOR inhibitors

• Patients must not be on strong inhibitors or inducers of CYP3A4 within two weeks prior to start of study treatment and for the duration of study treatment

• Patients should stop using herbal medications at least 7 days prior to the first dose of copanlisib. Herbal medications include, but are not limited to: St. John's Wort, Kava, ephedra, gingko biloba, dehydroepiandrosterone (DHEA), yohimbe, saw palmetto, black cohosh and ginseng

• Patients with type I or II diabetes mellitus must have a hemoglobulin (Hb) A1c ≤ 8.5% within 28 days from registration

• Patients must not have uncontrolled hypertension defined as systolic blood pressure (SBP) greater than 160 mmHg or diastolic blood pressure (BP) greater than 100 mmHg or use of more than 2 anti-hypertensive medications

• Patients must not have HER2 positive (3+ by IHC or fluorescence in situ hybridization [FISH] ratio ≥ 2) breast cancer

• Patients must not have indolent NHL (Non-Hodgkin's Lymphoma) or DLBCL (diffuse large B cell lymphoma) because other studies are ongoing with this agent in this group patients

• Patients must not be on anti-arrhythmic therapy other than digoxin or beta-blockers

• Absolute neutrophil count (ANC) ≥ 1.5 x 10^9 /L

• Platelets ≥ 100x10^9 /L

• Hemoglobulin (Hgb) > 9 g/dl

• Total serum bilirubin < 2.0 mg/dL

• Aspartate aminotransferase (ALT) and Alanine aminotransferase (AST) < 2.5 x upper limit of normal (ULN) (< 5 x ULN in patients with liver metastases)

• Serum creatinine < 1.5 x ULN

• Patients with non-healing wound, ulcer, or bone fracture are not eligible

• Patients with history of or current interstitial pneumonitis are not eligible. NOTE: For solid tumors, CMV PCR can be obtained at the discretion of treating physician or local institutional guidelines

• Patients must agree not to conceive or father children by agreeing to use contraception while receiving study treatment and for 1 month after the last dose of copanlisib