A Trial of the Safety and Immunogenicity of the COVID-19 Vaccine (mRNA-1273) in Participants With Hematologic Malignancies and Various Regimens of Immunosuppression, and in Participants With Solid Tumors on PD1/PDL1 Inhibitor Therapy

Design of the Study:

This is an open-label, multicenter clinical trial designed to evaluate the safety, reactogenicity and primary immunogenicity of the messenger ribonucleic acid (mRNA)-1273 vaccine administered in 2 doses, 28 days apart, in participants who have hematological malignancy and are immunosuppressed due to their disease and/or treatment or receiving a Programmed cell death protein 1 (PD-1)/Programmed death-ligand 1 (PDL-1) inhibitor for treatment of a solid tumor can be associated with appropriately high rates of development of neutralizing antibodies of mRNA-1273. The trial will also evaluate the safety, reactogenicity and immunogenicity after administration of additional booster doses of the vaccine.

Study Phase:

Study Population:

For the vaccine-na(SqrRoot) ve cohorts, up to 80 participants will be enrolled.

• 20 participants with solid tumor malignancies who have initiated PD1/PDL1 inhibitor therapy as part of standard of care and are deemed to have a stable regimen without the need for any immunosuppressive therapy or corticosteroids.
• 60 participants with leukemia, lymphoma, multiple myeloma and participants post-allogeneic stem cell transplant will be enrolled based on their perceived risk of immunosuppression.

For the previously-vaccinated (also known as "booster") cohorts, up to 140 participants will be enrolled for booster injections. All participants on the vaccine-na(SqrRoot) ve cohorts will have the option of receiving boosters; however, they will not count towards the maximum accrual goal for each of the booster groups. Note: All participants will be eligible to receive up to three (3) booster doses of vaccine on study.

• 20 participants with solid tumor malignancies who have initiated PD1/PDL1 inhibitor therapy as part of standard of care and are deemed to have a stable regimen without the need for any immunosuppressive therapy or corticosteroids.
• 20 participants with chronic lymphocytic leukemia who are not currently on any therapies
• 20 participants with chronic lymphocytic leukemia who are on Bruton's tyrosine kinase (BTK) inhibitor therapy alone
• 30 participants with any chimeric antigen receptor (CAR) T Cell therapy for a hematologic malignancy
• 20 participants post-allogeneic stem cell transplant
• 20 participants with other hematologic malignancies
• Up to 10 participants with any solid tumor who are not otherwise eligible for any of the other cohorts

Number of Sites: 2

Description of Study Product or Intervention:

mRNA-1273 Injection (Drug Product) is an lipid nanoparticles (LNPs) dispersion containing a single mRNA sequence (Drug Substance) that encodes the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) S glycoprotein stabilized in the prefusion conformation. The mRNA-1273 Drug Substance is combined with a mixture of 4 lipids common to the Moderna's mRNA vaccine platform: SM-102 (a custom-manufactured, ionizable lipid) and 3 commercially available lipids, cholesterol, distearoylphosphatidylcholine (DSPC), and 1,2-dimyristoyl-rac-glycero-3-methoxypolyethylene glycol-2000 (PEG2000-DMG) (https://doi.org/10.1038/s41587-020- 00807-1). mRNA-1273 Injection is provided as a sterile solution for injection, white to off white dispersion in appearance.

Presentation: mRNA-1273 Injection is provided as a sterile solution for injection at a concentration of 0.2 mg/mL in 20 mM trometamol (Tris) buffer containing 87 mg/mL sucrose and 4.3 mM acetate, at potential hydrogen (pH) 7.5. mRNA-1273 Injection is presented in 10R USP Type I borosilicate glass vials with PLASCAP vial seal containing a 20 mm FluroTec-coated plug stopper and has a 6.3 mL nominal fill volume. This vial may be used for more than one participant.

mRNA-1273 Injection must be stored frozen at -15 degrees C to -25 degrees C until thawed for use and then stored refrigerated at 2 degrees C to 8 degrees C for up to 30 days (once thawed it must not be refrozen)

Each dose of 100 mcg (0.5 mL) will be administered via IM injection into the deltoid muscle on Days 1 and 29 (+/- 3 days) for the vaccine-na(SqrRoot) ve cohorts. Up to 3 additional (booster) doses of the vaccine may also be administered.

Study Objectives:

Primary:

• To evaluate the safety and reactogenicity of the mRNA-1273 vaccine administered in 2 doses, 28 days apart, in participants who have a hematological malignancy and are immunosuppressed due to their disease and/or treatment, or receiving a PD-1/PDL-1 inhibitor for treatment of a solid tumor for patients who are vaccine-na(SqrRoot) ve
• To evaluate the safety and reactogenicity of booster doses of mRNA-1273 vaccine administered to participants who have previously received an mRNA or alternative vaccine regimen
• To evaluate the safety and reactogenicity of booster doses of mRNA-1273 administered to participants with chronic lymphocytic leukemia (CLL) who are either off treatment or are engaging in a 3-week BTK inhibitor interruption to enhance vaccine immunogenicity
• To assess the immunogenicity of mRNA-1273 in participants with cancer, as assessed by the titer or level of specific binding antibody (bAb)

Secondary:

• To evaluate the immunogenicity of the mRNA-1273 vaccine administered in 2 doses 28 days apart, as assessed by the titer or level of neutralizing antibody (nAb) in the vaccine-na(SqrRoot) ve cohorts
• To evaluate the immunogenicity of booster doses of mRNA-1273 vaccine administered to participants who have previously been vaccinated against SARS-CoV2 with any prior vaccine regimen. as assessed by the titer or level of neutralizing antibody (nAb)

Exploratory:

• To assess immune responses against the SARS-CoV-2 nucleocapsid and spike proteins
• To evaluate salivary measurement of immunoglobulin G (IgG) antibodies against the SARS-CoV-2 nucleocapsid and spike (S) proteins

Duration of Individual Participant Participation:

The duration for each individual participation is approximately 14 months (from first contact to last visit).

Study Duration:

Study duration is anticipated to be 16 months (from start of screening to last Participant/last visit).

• INCLUSION CRITERIA:

Participants must meet all the inclusion criteria in order to be eligible to participate in the study.

Participants must have one of the following:

• Histologically or cytologically confirmed solid tumor receiving a standard of care programmed cell death protein 1 (PD1)/Programmed death-ligand 1 (PDL1) inhibitor for treatment of their solid tumor (inclusive of Hodgkin Lymphoma and Primary Mediastinal B-Cell Lymphoma participants receiving PD1/PDL1 inhibitors as standard of care therapy)
• Confirmed diagnosis of acute leukemia (myeloid (AML) or lymphoid (ALL) or other acute leukemia; multiple myeloma; Waldenstrom macroglobulinemia
• Confirmed diagnosis of lymphoma, including small lymphoblastic lymphoma (i.e.,chronic lymphocytic leukemia)

• Be post allogeneic stem cell transplantation (for any indication)
• Be an adult patient (aged 18 or older) with any malignancy who does not fit any of the above categories
• Age >=18 years.
• History of adequate organ and marrow function on a recent laboratory assessment (within 4 weeks of administration of vaccine), as defined below:
• Absolute lymphocyte count-Minimum value of 200 cells per mcL
• Absolute neutrophil count-Minimum value of 500 cells per mcL
• Platelets-Minimum value of 25,000 cells per mcL
• Total bilirubin-Maximum value of 3.0 x upper limit of normal
• Aspartate aminotransferase (AST) serum glutamic oxaloacetic transaminase (SGOT)/alanine transaminase ALT serum glutamic-pyruvic transaminase (SGPT)-Maximum value of 5.0 x upper limit of normal
• Creatinine-Maximum value of 3.0 x upper limit of normal (if elevated, use of creatinine calculated clearance will be necessary, as below)
• Creatinine clearance (only necessary for participants with elevated creatinine)-For participants with Chronic Kidney Disease, a calculated

Glomerular Filtration Rate minimum will be required as follows: >30 mL/min/1.73 m^2 for participants with creatinine levels above institutional normal.

• Participants with history of human immunodeficiency virus (HIV) may enroll
• Participants with history of chronic hepatitis B virus (HBV) must be on suppressive therapy (if indicated) with undetectable viral load.
• Participants with a known history of hepatitis C virus (HCV) infection must have been treated and cured with an undetectable HCV viral load. For participants with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load.
• A negative urine/serum pregnancy test for females of childbearing potential. The effects of mRNA-1273 Vaccine on the developing human fetus are unknown. For this reason, women of child-bearing potential and men must agree to use adequate contraception prior to study entry and for 30 days after the last study treatment.

Note: A female is considered to be of childbearing potential if she has experienced menarche and is not permanently sterile (i.e., hysterectomy, bilateral oophorectomy, or tubal ligation) or postmenopausal (postmenopausal is defined as 12 consecutive months with no menses without an alternative medical cause and with a serum follicle-stimulating hormone test result in the postmenopausal range).

Effective methods of contraception:

• Intrauterine device.
• Stable dose of hormonal birth control, such as those listed below, for at least 3 months prior to enrollment.

• Hormonal contraceptive tablets.
• Injectable hormonal contraceptives.
• Implanted hormonal contraceptives.
• Cutaneous contraceptive patches.
• Intravaginal hormonal contraceptive rings.

At least 1 barrier method. Effective barrier methods for use in this study are:

• Male or female condom.
• Diaphragm.
• Creams or gels that contain a chemical to kill sperm

If a female patient has a male participant who has had surgery to prevent pregnancy (vasectomy), that will be considered evidence of effective contraception.

• Ability to understand and the willingness to sign a written informed consent document.
• CLL participants undergoing Bruton tyrosine kinases inhibitors (BTKi) treatment interruption: Must be receiving treatment with a BTKi for 6 months prior to vaccination and be willing to hold their treatment for up to 3 weeks around the time of vaccination.

Exclusion criteria

All participants meeting any of the exclusion criteria at baseline will be excluded from study participation.

• Within 14 days of known exposure to someone with confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection or coronavirus disease (COVID-19).
• Acutely ill or febrile 24 hours prior to or at the Screening Visit (Day 0). Fever is defined as a body temperature greater than or equal to 38.0 degrees C/100.4 degrees F. Participants meeting this criterion may be rescheduled within the relevant window periods. Afebrile participants with minor illnesses can be enrolled at the discretion of the investigator.
• Participants on the vaccine na(SqrRoot) ve arms cannot have received any doses of the COVID-19

vaccine.

Participants who have not completed a standard vaccination series due to initiation of vaccination in a foreign location (e.g., single dose of Astra-Zeneca vaccine or a similar situation) may be enrolled after discussion with the principal investigator.

Participants on the booster arms must have received all doses of their initial COVID-19 vaccine (Participants vaccinated with the Janssen vaccine must have received the single dose of that Emergency Use Authorization (EUA) vaccine for COVID19, but all others must have received 2 doses) at least 4 weeks prior to vaccination on protocol. Participants will be allowed to enroll if they have already received booster doses of vaccine prior to enrolling on the protocol at least four weeks prior to vaccination on protocol. In this case, the protocol will administer a single booster dose of vaccination. Documentation will be required.

• Known diagnosis of chronic pulmonary disease (e.g., chronic obstructive pulmonary disease, asthma) that is not controlled.
• Chronic cardiovascular disease that is not controlled.
• Participants with a history of myocarditis (inflammation of the heart) or pericarditis (inflammation of the pericardium)
• History of anaphylaxis, urticaria, or other significant adverse reaction requiring medical intervention after receipt of a vaccine.
• Bleeding disorder considered a contraindication to intramuscular (IM) injection or phlebotomy.
• Participated in an interventional clinical trial with an investigational agent within 28 days prior to the Screening Visit (Day 0) or plans to do so while participating in this study. The site investigator may enroll a participant on the trial earlier than 28 days if enough time has passed to ensure that at least five half-lives have occurred.
• Prior/Concomitant Therapy

• Has received prior radiotherapy within 14 days before the first dose of study treatment. Participants must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis. A 7-day washout is permitted for palliative radiation (less than or equal to 2 weeks of radiotherapy) to non-central nervous system (CNS) disease.
• Has received a live vaccine within 30 days before the first dose of study treatment. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette-Guerin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (e.g., FluMist (registered trademark)) are live attenuated vaccines and are not allowed.
• Has received an inactivated vaccine within 14 days before the first dose of study treatment.
• Have major surgical procedures within 28 days or non-study-related minor procedures within 7 days before the first dose of study treatment. In all cases, the participant must be sufficiently recovered and stable before treatment administration.

--History of severe allergic reactions to any components of the study treatment.

• Has uncontrolled intercurrent illness, including but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, severe or ongoing interstitial lung disease (ILD), serious chronic gastrointestinal conditions associated with diarrhea, or psychiatric illness/social situations that would limit compliance with study requirement, substantially increase risk of incurring adverse events (AEs), or compromise the ability of the participant to give written informed consent.
• Active tuberculosis (clinical evaluation that includes clinical history, physical examination and radiographic findings, and tuberculosis testing in line with local practice).
• History of (non-infectious) pneumonitis that required steroids or has current pneumonitis.
• Has involvement in the planning and/or conduct of the study.
• Female who is pregnant or breastfeeding
• Male or female participant of reproductive potential who are not willing to employ effective birth control from screening to 30 days after the last dose of study treatment.