Clinical Trials

Inclusion Criteria:

• Part A - Have a histologically or cytologically confirmed metastatic solid tumor for which there is no available therapy that may convey clinical benefit.
• Part B – Have 1 of the following histologically or cytologically confirmed tumor types:
  • HNSCC that is considered incurable by local therapies. Subjects should have progressed after receiving platinum-containing systemic therapy. Systemic therapy given as part of multimodal treatment for locally advanced disease is allowed. The eligible primary tumor locations are oropharynx, oral cavity, hypopharynx, and larynx. Subjects may not have a primary tumor site of nasopharynx (any histology). Subjects enrolled in the PD-1-treatment-naïve HNSCC cohort may not have been treated with prior anti-PD-1/PD-L1 therapy.
  • Subjects enrolled in the PD-1-treatment-failure HNSCC cohort must be refractory to an FDA approved anti-PD-1/PD-L1 monoclonal antibody (mAb) as either monotherapy or in combination with other approved checkpoint inhibitors or other therapies according to their label, defined as (subjects must meet all of the following criteria):
    • Have received at least 2 doses of anti-PD-1/PD-L1 mAb.
    • Have progressive disease after anti-PD-1/PD-L1 mAb defined according to RECIST 1.1. The initial evidence of PD is to be confirmed by a second assessment, no less than 4 weeks from the date of the first documented PD, in the absence of rapid clinical progression.
    • Note:  this determination is made by investigator. If PD is confirmed, the initial date of PD documentation will be considered the date of disease progression.
    • Have documented PD within 24 weeks of the last dose of anti-PD-1/PD-L1 mAb. Patients who were re-treated with anti-PD-1/PD-L1 mAb and patients who were on maintenance with anti-PD-1/PD-L1 mAb will be allowed to enter the trial as long as there is documented PD within 24 weeks of the last treatment date (with anti-PD-1/PD-L1 mAb).
  • Adenocarcinoma of the stomach and/or gastric-esophageal junction (GEJ) that is considered inoperable and that has received, and progressed on, at least 1 prior chemotherapy regimen or HER2/neu-targeted approved therapy (if HER2/neu-positive). In both cases, subjects must not have been treated with prior anti-PD-1/PD-L1 therapy.
  • CRC for Arm 1 and Arm 2: CRC originating in either the colon or rectum that is locally advanced unresectable or metastatic (i.e., Stage IV) and that has received, and progressed on, all available standard-of-care therapies including fluoropyrimidine, oxaliplatin, and irinotecan but has not been treated with prior anti-PD-1/PD-L1 therapy.
  • CRC for Arm 3 and Arm 4: CRC originating in either the colon or rectum that is locally advanced unresectable or metastatic (i.e., Stage IV) and has been treated with ≤1 line of systemic therapy but has not been treated with prior anti-PD-1/PD-L1 therapy. Subjects eligible to receive EGFR-targeted therapy must have previously received this treatment in order to be eligible for the study.
    • Note – Subjects with known MSI high or MMR deficient gastric cancer or CRC (as determined by either PCR or IHC) are excluded from participating in this study. MSI high is defined as at least 2 allelic shifts occurring among the 5 analyzed microsatellite markers as detected by PCR. MMR deficient is defined as loss of expression of at least 1 of 4 proteins (MLH1, MSH2, MSH6, and/or PMS2) by IHC. If a subject’s MSI status is unknown, testing is not required to determine eligibility.
    • Note – Subjects who have withdrawn from standard treatment due to unacceptable toxicity warranting discontinuation of that treatment and precluding retreatment with the same agent before progression of disease will also be eligible.
    • Note – Subjects with CRC enrolled into Arm 3 or Arm 4 are not eligible to be re-enrolled in the study on Arm 1 or Arm 2 following discontinuation.
• Have measureable disease by irRECIST 1.1 criteria.
• Be ≥ 18 years of age on the day of signing informed consent.
• Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) Performance Scale.
• Demonstrate adequate organ function as defined in Table 3 (labs to be obtained within 7 days of initiation of treatment).
• If female of childbearing potential, have a negative urine or serum pregnancy test within 72 hours prior to receiving the first dose of study medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
• If female of childbearing potential, be willing to use an adequate method of contraception. Contraception, for the course of the study through 120 days after the last dose of study medication.
  • Note: Abstinence is acceptable if this is the usual lifestyle-preferred contraception for the subject.
• Male subjects are eligible to participate if they agree to the following during the intervention period and for at least 95 days after the last dose of chemotherapy or 7 days after the last dose of lenvatinib, whichever occurs last:
  • Be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis) and agree to remain abstinent; OR
  • Must agree to use contraception unless confirmed to be azoospermic (vasectomized or secondary to medical cause) as detailed below:
  • Agree to use a male condom plus partner use of an additional contraceptive method when having penile-vaginal intercourse with a WOCBP who is not currently pregnant.
  • Note: Men with a pregnant or breastfeeding partner must agree to remain abstinent from penile-vaginal intercourse or use a male condom during each episode of penile-vaginal penetration.
• Voluntarily agree to participate by giving written informed consent/assent for the trial. The subject may also provide consent/assent for Future Biomedical Research. However, the subject may participate in the main trial without participating in Future Biomedical Research.
• Submit an evaluable baseline tumor sample for PD-L1 analysis (either a newly obtained or archival tumor sample) as specified in the Procedure Manual.

Exclusion Criteria:

• Has had chemotherapy, radiation, or biological cancer therapy within 4 weeks prior to the first dose of study therapy, or who has not recovered to CTCAE Grade 0 or 1 from the AEs due to cancer therapeutics administered more than 4 weeks earlier (this includes subjects who received previous immunomodulatory therapy with residual immune-related adverse events [irAEs]). Subjects receiving ongoing replacement hormone therapy for endocrine irAEs will not be excluded from participation in this study.
  • Note: Subjects with Grade 2 neuropathy are excluded from Arm 3 of Part B but may be eligible for all other arms of Part B.Is currently participating and receiving study therapy, or has participated in a study of an investigational agent and received study therapy, or used an investigational device within 4 weeks of the first dose of study treatment.
• Has received previous treatment with another agent targeting the LAG-3 receptor.
• Has received previous treatment with an immunomodulatory therapy (i.e., anti-PD-1/PD-L1 or CTLA-4 agent) and was discontinued from that therapy due to a Grade 3 or higher irAE.
• Is expected to require any other form of antineoplastic therapy while on study.
• Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy in excess of replacement doses, or on any other form of immunosuppressive medication. Subjects (i.e., with asthma) that require intermittent use of bronchodilators, inhaled steroids, or local steroid injections would not be excluded from the study.
• Has a history of a previous, additional malignancy, unless potentially curative treatment has been completed, with no evidence of malignancy for 5 years.
  • Note: The time requirement for no evidence of disease for 5 years does not apply to the tumor for which a subject is enrolled in the study. The time requirement does not apply to subjects who underwent successful definitive resection of basal cell carcinoma of the skin, superficial bladder cancer or in situ cervical cancer, or other in situ cancers.
• Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases may participate provided they are radiologically stable; i.e., without evidence of progression for at least 4 weeks by repeat imaging
  • Note that the repeat imaging should be performed during study screening, clinically stable and without requirement of steroid treatment for at least 14 days prior to first dose of trial treatment.
• Has had a severe hypersensitivity reaction to treatment with another monoclonal antibody.
• Has an active autoimmune disease or a documented history of autoimmune disease, except vitiligo or resolved childhood asthma/atopy. Replacement therapy (i.e., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
• Has an active infection requiring therapy.
• Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis.
• Has had a prior stem cell or bone marrow transplant.
• Has a known history of or screens positive for Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies), or an active chronic or acute Hepatitis B (i.e., hepatitis B surface antigen [HBsAg] reactive) or Hepatitis C infection (i.e., hepatitis C virus [HCV] RNA [qualitative] is detected).
• Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the subject’s participation for the full duration of the study, or is not in the best interest of the subject to participate, in the opinion of the treating investigator.
• Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
• Is a regular user as determined by investigator judgment (including "recreational use") of any illicit drugs or has a recent history (within the last year) of substance abuse (including alcohol), at the time of signing informed consent.
• Has symptomatic ascites or pleural effusion. A subject who is clinically stable following treatment for these conditions (including therapeutic thoraco- or paracentesis) is eligible.
• Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 120 days after the last dose of trial treatment.
• Has clinically significant heart disease that affects normal activities.
• Has had major surgery in the past 4 weeks.
• Has received a live-virus vaccine within 30 days of planned treatment start. Seasonal flu vaccines that do not contain live virus are permitted.
• Subjects being considered for enrollment into Arm 4 with CRC in Part B are also excluded if any of the following additional criteria apply:
  • Has plans to use, or is using, any herbal medications/supplements or any medications or foods that are strong inhibitors or inducers of cytochrome P450 3A 4/5 ≤1 week prior to the start of study treatment.
  • Has received previous treatment with irinotecan.
  • Has a known diagnosis of Gilbert’s Syndrome.
• Prolongation of QTcF interval to > 480 ms.
• NOTE: If the QTcF is prolonged to > 480 ms in the presence of a pacemaker, contact the Sponsor to determine eligibility.

Eligibility last updated 10/7/21. Questions regarding updates should be directed to the study team contact.