A Study of Alectinib and Duvelisib in People With Anaplastic Lymphoma Kinase-Positive Anaplastic Large Cell Lymphoma (ALK+ALCL)

Inclusion Criteria:

• Pathologically-confirmed diagnosis of ALK+ ALCL by WHO/ICC, classificationprocedures in use at the time of diagnosis. Note that ALK+ ALCL by definitionexpresses ALK, which is readily detectable on standard IHC. Confirmation throughmolecular sequencing of the specific ALK translocation and fusion partner is notnecessary for enrollment.

• Relapsed or refractory disease after at least one line of prior systemic therapy.

• NOTE: Prior systemic therapy must have included at least one cytotoxicchemotherapy agent.

• NOTE: Prior treatment with an ALK inhibitor is allowed.

• NOTE: Patients being treated with an ALK inhibitor immediately prior toenrollment are eligible. This includes patients on an ALK inhibitor who are inclinical remission at the time of enrollment, as long as the patient is notimmediately planned for allogeneic transplant.

• NOTE: If the last therapy was an ALK inhibitor, the patient must not havestopped the ALK inhibitor and maintained clinical remission (no relapse) withno intervening therapy for ≥ six months.

• NOTE: Prior progression on ALK inhibitor is not specifically exclusionarythough should be reviewed with the MSK Principal Investigator.

• Age ≥ 18 years at the time of enrollment

• ECOG performance status ≤ 2 at the time of enrollment.

• Laboratory criteria:

• Absolute neutrophil count ≥ 1.0 K/mcL or ≥ 0.5 K/mcL if due to lymphoma (NOTE:growth factor is allowed).

• Platelet count ≥ 75 K/uL.

• Calculated creatinine clearance ≥ 60 mL/min by Cockcroft-Gault.

• Total bilirubin ≤ 2x upper limit of normal (ULN) or ≤ 3x ULN if due tohepatobiliary involvement with lymphoma, or ≤ 3x ULN if history of Gilbert'sdisease.

• Aspartate (AST) and alanine (ALT) aminotransferase ≤ 3 x ULN or ≤ 5x ULN if dueto hepatobiliary involvement with lymphoma.

• NOTE: Patients with AST and/or ALT > 3x ULN and total bilirubin > 2x ULN mustbe reviewed with the MSK Principal Investigator to determine eligibility.

• NOTE: Patients must meet laboratory criteria prior to initiation of thealectinib lead-in cycle and prior to initiation of combination therapy withduvelisib

• Able to swallow pills.

• Able to take prophylactic medications against Pneumocystis jirovecii pneumonia (PJP)

• Women of reproductive potential must have a negative serum or urine β humanchorionic gonadotropin (β-HCG) pregnancy test within 14 days before initiatingtherapy.

• Females of childbearing age must be on effective contraception per institutionalstandards during the treatment period and for 5 weeks after the last dose of thestudy drugs.

• Males must consistently use an effective contraception method per institutionalstandards during the treatment period and for 3 months following the last dose ofthe study drugs.

Exclusion Criteria:

• Prior allogeneic stem cell transplant within 6 months of starting treatment orpatients with active graft versus host disease (GVHD).

• Previous systemic anti-cancer therapy for ALK+ ALCL within 7 days of initiatingstudy drug

• NOTE: Systemic corticosteroids are allowed and must be tapered to 10 mg/day orless (prednisone equivalent) upon start of investigational treatment.

• NOTE: Patients who have received localized radiotherapy as part of immediateprior therapy may be allowed to enroll with shorter washout period afterdiscussion with the MSK Principal Investigator.

• NOTE: Prior progression on ALK inhibitor is not specifically exclusionarythough should be reviewed with the MSK Principal Investigatory.

• Ongoing use of immunosuppressant medications, including corticosteroids greater than 10 mg of prednisone or equivalent at the time of enrollment.

• Prior gastrointestinal condition or surgery that may, in the investigator'sjudgment, adversely affect drug absorption.

• Active viral infection with hepatitis B or hepatitis C. For hepatitis B, patientswho are seropositive (hepatitis B core Ab positive) are permitted if HBV DNA isnegative by PCR. For hepatitis C, patients who are seropositive (hepatitis C Abpositive) are eligible if HCV DNA is negative by PCR and curative therapy has beencompleted. o NOTE: Patients with HIV infection are permitted to enroll but are required to beon antiretroviral regimens that are in accordance with the current InternationalAIDS Society guidelines on concurrent use with chemotherapy. Use of experimentalantiretroviral agents or those containing zidovudine or ritonavir, cobicistat orsimilar potent CYP3 inhibitors are prohibited. In order to be eligible, patientstaking zidovudine or ritonavir, or cobicistat or other CYP3 inhibitors must changeto a different regimen 7 days prior to therapy initiation. Subjects must be on HAARTfor at least 12 weeks prior to therapy.

• Concurrent malignancy requiring active therapy within the last 2 years with theexception of basal cell or squamous cell carcinoma limited to the skin, carcinoma insitu of the cervix, breast or localized prostate cancer. Adjuvant or maintenancetherapy to reduce the risk of recurrence or other malignancy is permissible afterdiscussion with the Principal Investigator.

• Active cytomegalovirus (CMV) as defined by positive CMV PCR with clinicalmanifestations consistent with active CMV infection and requiring therapy. Carrierswill be managed as per institutional guidelines.

• Patients should not be on CYP4503A inhibitors or inducers at the time of treatmentinitiation.

• Pregnant or breastfeeding women.

• Any serious or unstable medical condition, laboratory abnormality, or psychiatricillness that would prevent the patient from signing informed consent or, in theinvestigator's judgment, increase the risk to the patient associated withparticipation in the study